Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis Nobuyuki Hamada *, Yuki Fujimichi Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), 2-11-1 Iwadokita, Komae, Tokyo 201-8511, Japan

A R T I C L E Keywords: Crystalline lens Ionizing radiation DNA repair factors Nontargeted effects Inflammation Tumor suppressors

I N F O

A B S T R A C T

Ionizing radiation is a proven human carcinogen and cataractogen. The crystalline lens of the eye is among the most radiosensitive tissues in the body. A clouding of the normally transparent lens (i.e., cataract) is very common. Conversely, the lens continues to grow throughout life without developing tumors, suggesting that the lens possesses strong anti-carcinogenesis mechanisms. There is mounting evidence that mutations of oncogenes, tumor suppressor genes, DNA repair genes involved in base excision repair, nucleotide excision repair, and DNA double-strand break repair, and genes involved in intercellular interactions (e.g., via connexin gap junctions), and inflammation affect cataract development. Associations of these factors with cancer have long been recognized, highlighting that cataractogenesis shares some common mechanisms with carcinogenesis. This paper briefly overviews the current knowledge on the potential involvement of tumor related factors, DNA repair factors, intercellular interactions and inflammation in spontaneous cataractogenesis, and discusses its implications for cataractogenesis induced by targeted and nontargeted effects of ionizing irradiation. © 2015 Elsevier Ireland Ltd. All rights reserved.

Abbreviations: A-bomb, atomic-bomb; Acvr1, activin A type 1 receptor; AP, apurinic/apyrimidinic; APE1, apurinic/apyrimidinic endonuclease 1; AQP, aquaporin; Arf, alternative reading frame; ATM, ataxia telangiectasia mutated; BER, base excision repair; Bin3, bridging integrator 3; Brca1/2, breast cancer susceptibility gene 1/2; Brg1, Brahma-related gene 1; BLM, Bloom syndrome RecQ helicase-like; BS, Bloom syndrome; BubR1, budding uninhibited by benzimidazoles-related 1; CKO, conditional knockout; c-Maf, cellular homologue of avian retrovirus musculoaponeurotic fibrosarcoma oncogene; CNS, central nervous system; CNV, copy number variation; Cox-2, cyclooxygenase 2; Cry, crystallins; CSA, Cockayne syndrome group A; CSB, Cockayne syndrome group B; CSF2, colony stimulating factor 2; CtIP, C-terminal binding protein-interacting protein; Cx, connexin; DLAD, DNase II-like acid DNase; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; 5′-dRP, 5′-deoxyribose-5-phosphate; DSB, DNA double-strand break; E2F1, E2F transcription factor 1; EphA2, Eph receptor tyrosine kinase type A2; ERCC6, excision repair cross-complementation group 6; FasL, Fas ligand; FEN1, flap endonuclease 1; FGF, fibroblast growth factor; γH2AX, phosphorylated histone H2AX; GJIC, gap junctional intercellular communication; GJ, gap junction; GST, glutathione S-transferase; GSTM1, glutathione S-transferase μ 1; GSTP1, glutathione S-transferase π 1; GSTT1, glutathione S-transferase ζ 1; GZ, germinative zone; HMGA1, highmobility group AT-hook 1; HPV16, human papilloma virus type 16; HR, homologous recombination; Hsf4, heat shock transcription factor 4; HSP, heat shock protein; ICRP, International Commission on Radiological Protection; IFI27, interferon α inducible protein 27; IL, interleukin; Ink4a, inhibitor of kinase 4a; IR, ionizing radiation; Kip1/2, kinase inhibitory protein 1/2; KO, knockout; LEC, lens epithelial cell; LET, linear energy transfer; LFC, lens fiber cell; LIG1, DNA ligase I; LIG3α, DNA ligase IIIα; LLR, longlived radical; LTCC, l-type calcium channel; MCP-1, monocyte chemoattractant protein 1; mgRb, retinoblastoma minigene; MMP-2, matrix metalloproteinase 2; MΦ, macrophage; NanogP8, Nanog homeobox pseudogene 8; Nbn, nibrin; NBS1, Nijmegen breakage syndrome 1; Ncoa6, nuclear receptor coactivator 6; NDRG2, N-Myc downstream regulated gene 2; NEIL1, Nei endonuclease VIII-like 1; NER, nucleotide excision repair; NF2, neurofibromin 2; NHEJ, nonhomologous end joining; NTE, nontargeted effect; OCDL, oxidatively induced clustered DNA lesion; OGG1, 8-oxoguanine glycosylase 1; 3’-P, 3′-phosphate; Pax6, paired box gene 6; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidyl inositol 3-kinase; Polβ, DNA polymerase β; 6-4PP, (6-4) photoproduct; PSC, posterior subcapsular; Pten, phosphatase and tensin homolog; 3’-PUA, 3′-phosphoα,β-unsaturated aldehyde; RANTES, regulated upon activation normal T-cell expressed and secreted; Rb, Retinoblastoma; RFC, replication factor C; RNS, reactive nitrogen species; ROS, reactive oxygen species; RPA, replication protein A; RTS, Rothmund–Thomson syndrome; sCLU, secretory clusterin; SIRT1, silent information regulator T1; SSB, DNA single-strand break; ssDNA, single-stranded DNA; Stat3, signal transducer and activator of transcription 3; SV40, simian virus 40; SWI/SNF, switch/sucrose nonfermentable; TFIIH, transcription factor II H; TGFβ1, transforming growth factor β1; TNF-α, tumor necrosis factor α; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; UV, ultraviolet light; VIC, vision-impairing cataract; Waf1/Cip1, wild-type p53-activated fragment 1/cyclin dependent kinase interacting protein 1; WRN, Werner syndrome helicase; WS, Werner syndrome; XLF, XRCC4-like factor; XPC, xeroderma pigmentosum complementation group C; XPD, xeroderma pigmentosum complementation group D; XRCC1, x-ray cross-complementing group 1. * Corresponding author. Tel.: +81 3 3480 2111; fax: +81 3 3480 3113. E-mail address: [email protected] (N. Hamada). http://dx.doi.org/10.1016/j.canlet.2015.02.017 0304-3835/© 2015 Elsevier Ireland Ltd. All rights reserved.

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Fig. 1. A schema depicting possible changes in carcinogenesis mechanism-related molecules and events that facilitate spontaneous cataractogenesis. Orange-highlighted areas represent increased gene expression or increased frequency of events, and blue-highlighted areas represent decreased gene expression or decreased frequency of events. For details, see sections ‘Role of tumor related factors in cataractogenesis’, ‘Role of DNA repair factors in cataractogenesis’, ‘Role of intercellular interactions in cataractogenesis’ and ‘Role of inflammation and other immune responses in cataractogenesis’. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Recent upsurge of interest in ionizing radiation (IR) cataracts Ever since the discovery of X-rays in 1895, IR has been indispensable in medicine and industry. Whereas human IR cataracts have been described since 1903 [1], the observation of atomic-bomb (A-bomb) and cyclotron cataracts in the late 1940s brought a surge of interest [2,3]. The International Commission on Radiological Protection (ICRP) listed cataracts as a radiation health hazard in 1950 [4] and recommended the first dose limit for the lens of the eye in 1954 [5]. In 2011, ICRP recommended lowering the thresholds for vision-impairing cataract (VIC) from 5 Gy for a single, brief exposure and >8 Gy for highly fractionated or protracted exposures to 0.5 Gy and the occupational equivalent dose limit for the lens from 150 mSv/year to 20 mSv/year (100 mSv in defined 5 years with no single year exceeding 50 mSv) [6], which were revised 27 and 31 years respectively after the previous revision [7]. Such reductions may affect some medical or nuclear workers (and perhaps patients as well) [8], thereby stimulating a resurgence of interest in cataracts. ICRP concluded that cataract is a tissue reaction with a threshold albeit small, and deduced a threshold dose from epidemiological data documenting no threshold [6]. This stimulated a debate as to whether cataracts are of stochastic nature without threshold [9–11], thus necessitating more mechanistic knowledge to justifiably classify cataracts as tissue reactions or stochastic effects [12]. In radiotherapy, the lens dose is kept to a minimum, where 10 Gy and 18 Gy are judged as tolerance dose that produces cataracts needing surgical intervention in 5% and 50% of patients respectively within 5 years post therapy [13] (c.f., an ICRP threshold of 0.5 Gy producing VIC in 1% of exposed individuals with >20 years followup [6]). Notwithstanding, children with retinoblastoma often receive radiotherapy because of its radiosensitive nature, leading to cataracts for which pediatric surgery is a challenge [14]. IR cataract is also a concern for long-term interplanetary manned missions [15], but mitigators have yet to be established because mechanisms

behind IR cataractogenesis remain incompletely understood. Its mechanisms therefore need to be further clarified. Here, we briefly overview the current knowledge on the potential involvement of tumor related factors, DNA repair factors, intercellular interactions and inflammation in spontaneous cataractogenesis (see sections ‘Role of tumor related factors in cataractogenesis’, ‘Role of DNA repair factors in cataractogenesis’, ‘Role of intercellular interactions in cataractogenesis’ and ‘Role of inflammation and other immune responses in cataractogenesis’, and Fig. 1), and discuss its implications for cataractogenesis induced by targeted effects and nontargeted effects (NTEs) of IR (see section ‘Implications for IR cataractogenesis’ and Fig. 2). Cataracts and unique features of the lens A cataract is a clouding or opacity of the normally transparent lens. Cataract is the leading cause of visual impairment and blindness worldwide [16], among which age related cataracts (hereinafter referred to as senile cataracts) are most common. Inherited childhood/juvenile cataracts (hereafter congenital cataracts) also occur, and several factors such as IR and ultraviolet light (UV) are proven to increase a risk of cataracts. The lens helps focus light onto the retina to form a sharp image and changes shape to adjust the focal length. Lenticular vasculature regresses prenatally in humans and before eye opening in rodents [17]. The cell nucleus and all other organelles undergo degradation during differentiation from cuboidal lens epithelial cells (LECs) into lens fiber cells (LFCs) that compose the bulk of the lens. Crystallins (Cry) are the major lens structural, water-soluble proteins [18]. The lens is proficient in physical intercellular contacts and physiological intercellular exchanges between adjoining cells mediated by connexin (Cx) gap junctions (GJs), aquaporin (AQP) water channels and various ion channels. Any impairment of these processes causes cataracts [19].

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Fig. 2. A hypothetical diagram of possible events that lead to ionizing radiation cataractogenesis. Red-colored arrows indicate responses following acute exposure, and bluecolored arrows indicate responses following protracted or chronic exposure. For details, see section ‘Implications for IR cataractogenesis’. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

The lens capsule, lens epithelium, lens cortex and lens nucleus constitute the lens, and the interface between its anterior and posterior surfaces is called an equator [20]. The lens epithelium consists of a single layer of LECs located in the anterior subcapsular region. LECs in the germinative zone (GZ) around the equator divide, migrate posteriorly, and differentiate into elongated LFCs. Newly formed LFCs surround existing cortical LFCs and become more internalized, culminating in production of highly ordered, tightly packed mature nuclear LFCs. A relatively thick basement membrane called the lens capsule encases the lens and physically sequesters the lens cells from other ocular structures. Due to its avascular nature, the lens capsule functions as the only filter for the transport of water, nutrients, metabolites and signaling molecules between the lens and other ocular structures [21]. The lens growth continues throughout life (at a constant rate after the early postnatal phase [22]), but does not develop tumors spontaneously in mammals except for cats [19,23] and genetically engineered mice (see subsection ‘Lens tumorigenesis’). All lens cells are derived from a single cell type (i.e., LEC), and stay inside the lens capsule irrespective of whether cells are alive or dead. Role of tumor related factors in cataractogenesis Lens tumorigenesis In mice, simian virus 40 (SV40) T antigen transgene [24] and the human papilloma virus type 16 (HPV16) E6 and E7 transgene [25], both of which inactivate p53 and Retinoblastoma (Rb, a transcription cofactor), cause lens tumor formation. A double conditional knockout (CKO) of p53 and activin A type 1 receptor (Acvr1, a type-1 bone morphogenetic protein receptor), but not a single knockout (KO) of p53 nor Acvr1 [26,27], leads to lens tumor development (Table 1). Thus, the lens can develop tumors when p53 and an additional other tumor suppressor are functionally impaired. In contrast to such genetically engineered mice, primary lens tumors are not

known in humans and any other species except for cats [19,23], implying that strong anti-carcinogenesis defense mechanisms avoid lens tumorigenesis under physiological conditions. Intriguingly, evidence is increasing suggesting the involvement of tumor related genes in cataractogenesis, which is overviewed below and in Table 1. Cataractogenesis and oncogenes This section discusses the role of oncogenes or its candidate genes of which activation or upregulation is correlated with a poor prognosis or exacerbates tumorigenesis. In mice, HPV16 E6 and E7 oncoproteins, Nanog homeobox pseudogene 8 (NanogP8, a tumor-specific retrogene) or inhibition of nuclear receptor coactivator 6 (Ncoa6, also called peroxisome proliferator-activator receptor interacting protein) increases cataracts [25,60,61]. Loss of signal transducer and activator of transcription 3 (Stat3) does not cause mouse cataracts [73]. Mice nullizygous or heterozygous for c-Maf (transcription factor) exhibit no cataracts, but its semi-dominant mutations are associated with congenital cataracts [30,31]. In humans, MAF mutations are associated with an increased risk of congenital cataracts [32–35]. Several studies but not all have shown that mice defective in Eph receptor tyrosine kinase type A2 (EphA2) develop cataract, and that EPHA2 variants or mutations are correlated with a higher risk of human congenital or senile cataracts (see Table 1 and references therein). Cataractogenesis and tumor suppressor genes This section discusses the role of tumor suppressor genes or its candidate genes of which inactivation or downregulation is correlated with a poor prognosis or exacerbates tumorigenesis. Rb KO mice are embryonic lethal, which is partially rescued by the use of a mouse Rb minigene (mgRb) [74]. Partially rescued Rb

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Table 1 Potential involvement of tumor-related genes in cataractogenesis. Genotypes

Phenotypes Lens tumorigenesis

Spontaneous cataractogenesis

Acvr1 Bin3−/− vs Bin3+/+ Brca2−/− vs Brca2+/+ c-Maf R291Q/+ vs c-Maf+/+ or c-Maf+/− c-Maf D90V/D90V or c-Maf D90V/+ vs c-Maf+/+ MAF mutations EphA2−/− vs EphA2+/+ EPHA2 variants or mutations

N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.

Ephrin-A5−/− vs Ephrin-A5+/+ GSTM1+ vs other genotypes GSTM1+GSTT1− vs other genotypes GSTM1− vs other genotypes

N.A. N.A. N.A. N.A.

GSTM1−GSTT1+ vs other genotypes GSTP1*A vs other genotypes GSTP1*B vs other genotypes GSTT1− vs other genotypes

N.A. N.A. N.A. N.A.

GSTT1*0/0 + 1/0 vs GSTT1* > 1/1 + 1/1 GSTT1* > 1/1 vs GSTT1*1/1 + 1/0 + 0/0 HPV16 E6 E7 transgene mgRb:Rb−/− vs mgRb:Rb+/− mgRb:Rb−/−p53−/− vs mgRb:Rb−/−p53+/+ mgRb:Rb−/−E2F1−/− vs mgRb:Rb−/−E2F1+/+ NanogP8 transgene Ncoa6 dominant negative inhibition or deletion NDRG2 upregulation NF2 mutations Pten−/− p16Ink4a−/−p19Arf−/− vs p16Ink4a+/+p19Arf+/+ p16Ink4a−/−BubR1H/H vs p16Ink4a+/+BubR1H/H p19Arf−/−BubR1H/H vs p19Arf+/+BubR1H/H p21Waf1/Cip1−/−BubR1H/H vs p21Waf1/Cip1+/+BubR1H/H p27Kip1mut/mut vs p27Kip1+/+ p27Kip1−/− vs p27Kip1+/+ p53−/−BubR1H/H vs p53+/+BubR1H/H p53CKOAcvr1+/+ or p53CKOAcvr1CKO vs p53+/+Acvr1+/+ p53CKOAcvr1CKO vs p53CKOAcvr1+/+ p57Kip2−/− vs p57Kip2+/+ SIRT1 upregulation SIRT1 downregulation Stat1−/− or Stat3d/d vs wild-type SV40 T antigen transgene

N.A. N.A. Mouse ↑ [25] N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. Mouse ↑ [27] N.A. N.A. N.A. N.A. Mouse ↑ [24]

Mouse ↑ [26] Mouse ↑ [28] Rat ↑ [29] Mouse ↑ [30] Mouse ↑ [31] Danish ↑ [32], human ↑ [33], Indian ↑ [34], Japanese ↑ [35] Mouse ↑ [36–38], Mouse − [39] American ↑ [40], American, Australian, British ↑ [36], American, Chinese, Indian ↑ [41], Australian ↑ [42], Australian, British, Chinese ↑ [43], Caucasian ↑ [44], Chinese ↑ [45,46] Human ↑ [47], Indian ↑ [48], Pakistani ↑ [49], Estonian − [50] Mouse ↑ [37,51] Chinese ↑ [52], Estonian ↑ [53], Italian − [54] Chinese ↑ [52] Asian ↑ and Caucasian − [55], Turkish female ↑ [56], Iranian non-smoker female ↑ [57], Italian − [54] Turkish female ↑ [56] Estonian ↑ [53] Estonian ↓ [53] Asian ↑ and Caucasian − [55], Chinese − [52], Estonian − [53], Iranian − [57], Turkish − [56] Chinese ↑ [58] Chinese ↓ [58] Mouse ↑ [25] Mouse ↑ [59] Mouse − [59] Mouse − [59] Mouse ↑ [60] Mouse ↑ [61] Human ↑ [62] Human ↑ [63] Mouse ↑ [64] Mouse ↑ [65] Mouse ↓ [66] Mouse ↑ [66] Mouse ↓ [67] Rat ↑ [68] Mouse − [69] Mouse ↑ [67] Mouse ↑ [27] N.A. Mouse ↑ [70] Human ↑ [71] Human ↑ [72] Mouse − [73] N.A.

CKO

N.A., not available. − /−, nullizygote. + /−, heterozygote. + /+, wild type. CKO, conditional knockout. H/H, hypomorphic (low level expression). mg, minigene. R291Q or D90V, amino acid substitutions. ↑, increased, accelerated or positively correlated. ↓, decreased, delayed or negatively correlated. − , not changed or not significant. Acvr1, activin A type1 receptor. Arf, alternative reading frame. Bin3, bridging integrator 3. Brca1, breast cancer susceptibility gene 1. BubR1, budding uninhibited by benzimidazoles-related 1. c-Maf, cellular homologue of avian retrovirus musculoaponeurotic fibrosarcoma oncogene. EPHA2, Eph receptor tyrosine kinase type A2. GSTM1, glutathione S-transferase μ 1. GSTP1, glutathione S-transferase π 1. GSTT1, glutathione S-transferase ζ 1. HPV16, human papillomavirus type 16. Ink4a, inhibitor of kinase 4a. Kip1/2, kinase inhibitory protein 1/2. mgRb, retinoblasoma minigene. NanogP8, Nanog homeobox pseudogene 8. Ncoa6, nuclear receptor coactivator 6. NDRG2, N-Myc downstream regulated gene 2. NF2, neurofibromin 2. Pten, phosphatase and tensin homolog. Rb, retinoblasoma. SIRT1, silent information regulator T1. Stat1/3, signal transducer and activator of transcription 1/3. SV40, simian virus 40. Waf1/Cip1, wild-type p53-activated fragment 1/cyclin dependent kinase interacting protein 1.

mutant mouse fetuses (mgRb:Rb−/−) exhibit cataracts, and cataract phenotypes do not change in such mutant mice additionally deficient in E2F transcription factor 1 (E2F1, a major partner of Rb) or p53 [59]. p16Ink4a, p19Arf, p21Waf1/Cip1 (Cdkn1a), p27Kip1 (Cdkn1b) and p57Kip2 (Cdkn1c) are cyclin dependent kinase inhibitors, and budding uninhibited by benzimidazoles-related 1 (BubR1) is the mitotic checkpoint protein [75]. Mice lacking both p16Ink4a and p19Arf develop cataract [65]. BubR1-insufficient mice manifest cataracts [75], which is alleviated by inactivation of p16Ink4a or p21Waf1/Cip1, but exacerbated by inactivation of p19Arf or p53 [66,67]. Whereas loss of p27Kip1 increases cataracts in rats [68], loss of p57Kip2 but not loss of p27Kip1 increases cataracts in mice [69,70], suggesting the major regulatory role of p57Kip2 in mouse cataractogenesis.

Acvr1 CKO mice occasionally harbor cataracts [26]. p53 CKO mice, and Acvr1;p53 double CKO mice, but not Acvr1 CKO mice, develop cataracts, and then Acvr1;p53 double CKO mice, but not p53 CKO mice, develop lens tumors [27]. Rats defective in breast cancer susceptibility gene 2 (Brca2), and mice defective in bridging integrator 3 (Bin3, a member of the BinAmphiphysin-Rvs domain super family) [28], Ephrin-A5 (a receptor protein tyrosine kinase), or phosphatase and tensin homolog (Pten, a protein tyrosine phosphatase) develop cataracts [28,29,37,51,64]. Stat1 deficiency does not cause cataracts in mice [73]. In humans, upregulation of N-Myc downstream regulated gene 2 (NDRG2) and mutations of neurofibromin 2 (NF2, an ezrin, radixin, moesin family cytoskeletal protein) are associated with a higher risk of senile cataracts and congenital cataracts, respectively [62,63].

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Cataractogenesis and other tumor related genes This section discusses the role of other tumor related genes or cancer-modifying genes of which function is controversial but inactivation appears to increase carcinogenesis. Silent information regulator T1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase that acts as a tumor suppressor in some cancers but as an oncogene in other cancers [76,77]. SIRT1 upregulation [71] or its downregulation [72] is associated with a higher risk of human senile cataracts. SIRT1 reduces p27Kip1 expression [78], but levels of both SIRT1 and p27Kip1 in human lenses with senile cataracts are higher than in cataract-free, age-matched control lenses [71]. Glutathione S-transferase (GST) is a family of detoxification enzymes, and its gene polymorphisms leading to partial or complete loss of enzymatic activity are correlated with a risk of some cancers [79] but not other cancers [80,81]. Several studies but not all have reported that polymorphisms of GSTM1, GSTP1 and GSTT1 are associated with an increased or decreased risk of human senile cataracts (see Table 1 and references therein).

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like 1 (NEIL1) excise a damaged base, incise the DNA backbone immediately 3′ to the AP site product, and produce an SSB with a 3′-phospho-α,β-unsaturated aldehyde (3′-PUA) or 3′-phosphate (3′P) group. AP endonuclease 1 (APE1) incises the AP site, creates a 5′-deoxyribose-5-phosphate (5′-dRP) and 3′-OH strand break product, and removes the 3′-PUA residue. DNA polymerase β (Polβ) removes the 5′-dRP moiety. In the short-patch BER, Polβ replaces the missing nucleotide, and x-ray cross-complementing group 1 (XRCC1)-DNA ligase IIIα (LIG3α) seals the nick. In the long-patch BER, Polδ/ε, replication factor C (RFC) and proliferating cell nuclear antigen (PCNA) incorporate 2–13 nucleotides and then flap endonuclease 1 (FEN1)-DNA ligase I (LIG1) completes the repair process. Some studies show that polymorphisms of OGG1 or XRCC1 are associated with an increased risk of human senile cataracts [82,104,110,111], but not other studies [82,89,92,108,109]. APE1 polymorphisms are not associated with a human senile cataract risk [82]. Polβ-overexpressing mice develop cataracts with concomitant increase in cyclooxygenase 2 (Cox-2) expression in LFCs [91]. Cataractogenesis and nucleotide excision repair (NER) genes

Role of DNA repair factors in cataractogenesis This section overviews growing evidence for involvement of DNA repair genes in cataractogenesis (Table 2). Cataractogenesis and base excision repair (BER) genes BER repairs non-bulky, non-helix-distorting base lesions, uracil, apurinic/apyrimidinic (AP) sites and DNA single-strand breaks (SSBs) [112]. The monofunctional DNA glycosylase removes the damaged base and creates an AP site. Bifunctional DNA glycosylases such as 8-oxoguanine glycosylase 1 (OGG1) and Nei endonuclease VIII-

NER repairs bulky, helix-distorting base lesions such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (64PP) [112]. In global genome NER, xeroderma pigmentosum complementation group C (XPC)-RAD23B recognizes DNA damage. Stalling of RNA polymerase II at a DNA lesion initiates transcription coupled NER, which in turn serves as a signal to engage Cockayne syndrome group A (CSA) and B [CSB, also known as excision repair cross-complementation group 6 (ERCC6)]. After recognition, the transcription factor II H (TFIIH) complex containing two helicases (i.e., XPB and XPD) facilitates opening of the DNA duplex around the lesion to promote recruitment of XPA and

Table 2 Potential involvement of DNA repair-related genes in cataractogenesis. Genotypes

APE1 polymorphisms Atm−/− or Atm+/− vs Atm+/+ Atm+/−Brca1+/− vs Atm+/+Brca1+/− or Atm+/−Brca1+/+ Atm+/−Rad9+/−, Atm+/−Rad9+/+ or Atm+/+Rad9+/− vs Atm+/+Rad9+/+ Atm+/−Rad9+/− vs Atm+/−Rad9+/+ or Atm+/+Rad9+/− Atm+/+Rad9+/− vs Atm+/−Rad9+/+ ATM haplotypes BLM polymorphisms Brca2−/− vs Brca2+/+ Brg1 dominant negative inhibition DNA polymerase β overexpression ERCC6 polymorphisms or copy number variations Hsf4−/− Hsf4 R116H transgene HSF4 mutations or copy number variations NbnCNS-Δ vs NbnCNS-control NbnCNS-Δp53−/− vs NbnCNS-Δp53+/+ OGG1 polymorphisms or copy number variations Recql4−/− WRN polymorphisms or copy number variations XPD polymorphisms XPD polymorphisms + XRCC1 polymorphisms XRCC1 polymorphisms

Phenotypes Spontaneous cataractogenesis

Ionizing radiation cataractogenesis

Chinese − [82] Mouse ↑ [83,84] N.A. Mouse ↑ [84] Mouse − [84] Mouse − [84] N.A. Chinese − [89] Rat ↑ [29] Mouse ↑ [90] Mouse ↑ [91] Chinese − [89,92] Mouse ↑ [93] Mouse ↑ [94] Chinese ↑ [92,95–98], Pakistani ↑ [99,100], Tunisian ↑ [101] Mouse ↑ [102,103] Mouse − [102] Chinese ↑ [82], Egyptian ↑ [104], Chinese − [89,92] Mouse − [105] Chinese ↑ [89,92,106], Israeli − [107] Egyptian ↑ [104], Indian ↑ [108], Turkish ↑ [109], Chinese − [82,110], Caucasian ↓, Asian − [111] Indian ↑ [108] Asian ↑, Caucasian − [111], Chinese ↑ [110], Chinese − [82], Indian − [108], Turkish − [109]

N.A. Mouse ↑ [83–86] Mouse ↑ [87] Mouse ↑ [84] Mouse ↑ [84] Mouse ↑ [84] Atomic bomb survivors ↑ [88] N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A.

N.A., not available. − /−, nullizygote. + /−, heterozygote. + /+, wild type. R116H, amino acid substitutions. ↑, increased, accelerated or positively correlated. ↓, decreased, delayed or negatively correlated. − , not changed or not significant. mg, minigene. APE1, apurinic/apyrimidinic endonuclease 1. Atm, ataxia telangiectasia mutated. BLM, Bloom syndrome RecQ helicase-like. Brca1/2, breast cancer susceptibility gene 1/2. Brg1, Brahma-related gene 1. CNS, central nervous system. ERCC6, excision repair crosscomplementation group 6. Hsf4 or HSF4, heat shock transcription factor 4. Nbn, nibrin. OGG1, 8-oxoguanine glycosylase 1. WRN, Werner syndrome helicase. XPD, xeroderma pigmentosum complementation group D. XRCC1, x-ray cross-complementing group 1.

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replication protein A (RPA). After dual incision by XPF-ERCC1 and XPG, DNA polymerase performs gap-filling repair synthesis in cooperation with RFC and PCNA. XRCC1-LIG3α or the FEN1-LIG1 seals the nick. Some studies show that XPD polymorphisms are associated with an increased risk of human senile cataracts [82,104,108–110], but other studies show associations with its decreased risk or no association [82,110,111]. Polymorphisms and copy number variations (CNVs) of ERCC6 are not associated with a risk of human senile cataracts [89,92]. Cataractogenesis and RecQ helicase genes Humans possess five RecQ helicases [113], among which defects in BLM and WRN cause Bloom syndrome (BS) and Werner syndrome (WS), respectively. Defects in RECQL4 cause Rothmund– Thomson syndrome (RTS), RAPADILINO syndrome and Baller– Gerold syndrome. WS or RTS patients manifest bilateral juvenile cataracts [114], and there is a case report for lens opacities in a BS patient [115]. BER, NER and DNA double-strand break (DSB) repair involve these RecQ helicases [113]. Three studies show that polymorphisms and CNVs of WRN are associated with an increased risk of human senile cataracts [89,92,106], but one study shows a lack of association [107]. BLM polymorphisms are not associated with a risk of human senile cataracts [89], and Recql4-decifient mice do not exhibit cataracts [105]. Cataractogenesis and DSB repair genes Homologous recombination (HR) or nonhomologous end joining (NHEJ) repairs DSBs [112,113]. HR occurs during the late S and G2 phases and is error free. MRE11, RAD50 and Nijmegen breakage syndrome 1 [NBS1, also called Nibrin (Nbn)] compose the MRN complex, which recruits ataxia telangiectasia mutated (ATM) to DSB sites and associates with the C-terminal binding protein-interacting protein (CtIP) for resection. RPA stabilizes the single-stranded DNA (ssDNA), and RAD52 is recruited to RPA. RAD52-RPA facilitates singlestrand annealing in a RAD52-independent manner. RAD51-BRCA2 replaces RAD52-RPA. D-loop formation follows Holliday junction formation or DNA synthesis-dependent strand annealing. BRCA1 is a pro-HR factor pivotal to the choice between HR and NHEJ [116,117]. NHEJ is error prone and predominantly independent of ATMdependent signaling and cell cycle. In canonical NHEJ, the Ku70/ Ku80 heterodimer binds to the two DSB ends and recruits DNAdependent protein kinase catalytic subunit (DNA-PKcs), which activates Artemis endonuclease. XRCC4-LIG4 conducts end joining in collaboration with XRCC4-like factor (XLF). Alternative NHEJ employs various factors that are also involved in other repair pathways (e.g., the MRN complex, CtIP and LIG3), and is active when canonical NHEJ is impaired. Lens opacities are reported in some NBS patients [118]. Nbndeficient mice develop cataracts due to abnormal LFC differentiation [102,103], and p53 does not rescue such cataract phenotype [102]. Genetic inactivation of Atm exacerbates the growth impairment of the Nbn-deficient mouse embryonic lens due to DSB accumulation and premature apoptosis [119], suggesting distinct roles of Atm and Nbn in the developing lens. Heat shock transcription factor 4 (Hsf4) upregulates Rad51 (an HR repair factor) [120]. Hsf4-null mice develop cataracts along with decreased γ-Cry expression and increased fibroblast growth factor (FGF) expression [93]. HSF4 mutations or CNVs are associated with an increased risk of human congenital or senile cataracts [92,95–101]. Of these, a substitution of arginine to histidine at codon 116 (R116H mutation) in HSF4 is associated with an increased risk of human senile cataracts [97], and its transgene causes cataracts in mice [94]. Mice defective in DNase II-like acid DNase (DLAD, also called DNase

2β) develop cataracts owing to impaired denucleation during lens cell differentiation [121], and Hsf4 increases expression and activity of DLAD [122]. Thus, the cataract phenotype of Hsf4-null mice seems likely to result at least in part from defects in DLAD. Brahma-related gene 1 (Brg1) encodes an ATP-dependent catalytic subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin via various mechanisms involving DNAbinding factor such as paired box gene 6 (Pax6) and Hsf4, nonhistone chromatin structural proteins such as high-mobility group AThook 1 (HMGA1), and acetylated core histones. Dominant negative inhibition of Brg1 leads to cataract formation in mice, and Brg1 is required for DLAD expression as well as for LFC differentiation and denucleation [90]. αA-Cry and αB-Cry are members of the small heat shock protein (HSP) family, and function as major lens structural proteins and molecular chaperones. High levels of αA-Cry are associated with an abundance of Brg1 recruited to the αA-Cry locus via Pax6 [123]. BRG1 activates the αB-Cry promoter, and HMGA1 mediates this process [124]. Hsf4 recruits Brg1 to HSP promoters during the G1 phase [125]. ATM-mediated BRG1 phosphorylation stimulates its association with nucleosomes containing phosphorylated histone H2AX (γH2AX), thus facilitating DSB repair [126]. Brg1 also promotes NER [127,128]. Atm+/– mice develop cataracts earlier than do wild types [83,84]. Atm–/– mice are most sensitive to IR-induced cataracts, and sensitivity of ATM+/– is intermediate between Atm–/– and wild types [85]. Compared with wild types, Atm+/– mice are more susceptible to cataracts induced by exposure to sparsely ionizing, low linear energy transfer (LET) photons (e.g., X-rays, γ-rays) and those by exposure to densely ionizing, high-LET heavy ions [83–86] of which biological effectiveness is greater than photons [129–131]. The mechanisms for greater biological effectiveness of high-LET radiation involve clustered DNA damage, where the insufficient repair and induction of genomic instability and other radiation effects may be associated with the repair-resistant DSBs and oxidatively induced clustered DNA lesions (OCDLs) [132]. ATM haplotypes appear to be associated with a risk of cataract surgery among A-bomb survivors [88]. Rad9 is required for the intra-S and G2 checkpoint, and involved in HR, BER, NER and mismatch repair [133]. Atm+/–, Rad9+/– and Atm+/–Rad9+/– mice similarly develop spontaneous cataracts earlier than wild types [84]. Atm+/–, Rad9+/– and Atm+/–Rad9+/– mice similarly develop photoninduced cataracts earlier than wild types, and such radiosensitivity of Rad9+/– is intermediate between Atm+/–Rad9+/– and Atm+/– [84]. Atm+/–Brca1+/– mice are more sensitive to photon-induced cataracts than Atm+/– and Brca1+/– [87]. However, the same research team has also reported that whereas Atm+/–Rad9+/– mice are markedly more sensitive than Atm+/– or Rad9+/–, Atm+/–Brca1+/– mice are no more sensitive than Atm+/– or Brca1+/– [134,135]. As described in subsection ‘Cataractogenesis and tumor suppressor genes’, Brca2-defective rats develop spontaneous cataracts [29]. Role of intercellular interactions in cataractogenesis Cataractogenesis, Cx and gap junctional intercellular communication (GJIC) GJIC is a unique route that allows direct exchange of small cytoplasmic molecules (e.g., ions and metabolites of <1 kDa) between contiguous cells. A hemichannel is a transmembrane Cx hexamer, and a GJ comprises two juxtaposed hemichannels each provided by adjacent cells. Among 21 human and 20 mouse Cx genes, Cx43, Cx46 and Cx50 play major roles in the lens. LECs in human and mouse lenses express Cx50 and Cx43, where Cx50 predominates during the early postnatal period and Cx43 subsequently becomes predominant [136]. Cx43 expression drops as differentiation proceeds, and LFCs express Cx46 and Cx50 [137]. Cx43-null mice possess

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loosely connected LECs and LFCs separated from apical surfaces of LECs, but do not develop cataracts [138]. Loss of Cx46 or Cx50 leads to cataract formation in mice, such that Cx46-deficient mice develop more severe cataracts than Cx50-deficient mice [139–141]. Mice harboring a missense mutation of Cx23 exhibit impaired elongation of primary LFCs and develop cataracts [142], but Cx23 expression is not detected in the human lens [143]. Mutations of Cx46 and Cx50 are associated with an increased risk of human congenital cataracts [144] and senile cataracts [145,146]. Cx plays a tumor suppressor role in suppressing cell growth, invasion and metastasis [147], but also plays opposite roles in promoting cell migration and apoptotic resistance [148].

not humoral immune response [167,168]. Experimental uveitis occurs following the lens capsule rupture by capsulotomy, but not following thermal cautery, lipopolysaccharide treatment or IR [168]. However, the contribution of inflammatory and other immune responses to the whole cataractogenesis processes may be minimal, because the eye possesses the properties of immune privilege that minimizes immune responses to preserve vision and provides the immunosuppressive microenvironment [169].

Cataractogenesis and AQP

IR cataract is a typical tissue reaction with a threshold below which no effect would occur [6]. This belief has prevailed since 1969 [170], but has recently been challenged by mounting epidemiological evidence documenting no threshold with a long-term follow up after IR exposure [6,8]. There has been a continuing discussion over whether IR cataracts are of stochastic nature with no threshold [9–11], but IR cataract production may involve several mechanisms. Human IR cataracts are typical late effects that reportedly take a few months to decades to appear [171,172]. Common IR cataracts are posterior subcapsular (PSC) cataracts, but cortical cataracts have also been associated with IR exposure [173,174]. It is noteworthy that whereas a latency period of PSC cataracts greatly differs from months to decades, cortical cataracts only appear many years after IR exposure. Take A-bomb cataracts for example. PSC cataracts were firstly described in 1949 (≤3 years after A-bombing) [2], and have still been described half century thereafter [175]. A significant threshold for A-bomb PSC cataracts was found at 11–12 years after exposure [176], but not from 18–19 years onward [177]. A-bomb cortical cataracts were firstly described in 2004 with an insignificant threshold [178]. Thus, different mechanisms may underlie production of early onset PSC cataracts with a threshold (e.g., cataracts taking months to years to appear) and late onset PSC or cortical cataracts with no threshold [179,180].

AQP is a family of water channel proteins composed of 13 isoforms (AQP0-AQP12) in mammals. AQP0 accounts for about half of LFC membrane proteins. AQP1 is expressed in LECs, and AQP5 is expressed in LECs and LFCs. AQP0 maintains tissue water balance and promotes cell adhesion. AQP0-mutated mice develop cataracts, and AQP0 mutations are associated with an increased risk of human congenital cataracts [149]. In mice, loss of AQP1 or AQP5 does not promote spontaneous cataracts, but accelerates cataractogenesis under high glucose conditions [150,151]. AQP also facilitates cell proliferation and migration, and is overexpressed in various cancers [152]. A link between Cx and AQP in the lens Calcium homeostasis is central to lens transparency, and an increased intracellular Ca2+ level in the lens contributes to human cortical cataracts [153]. Inhibition of l-type calcium channels (LTCCs) causes AQP0 phosphorylation and Cx50 upregulation, followed by cortical cataract formation [154]. In the lens, AQP0 enhances Cx50 GJs [155], and intracellular Ca2+ levels and calmodulin regulate GJs and AQP0 [156], suggesting a link between Cx, AQP and calcium signaling. Role of inflammation and other immune responses in cataractogenesis Acute inflammatory response functions to restore tissue injury caused by infection or other insults. In contrast, chronic inflammatory response promotes carcinogenesis and is one of the hallmarks of some solid tumors [157]. Scavenger macrophages (MΦ) exist in the developing lens, but after the lens cavity is filled, the lens capsule avoids MΦ entrance into the intact lens [158]. Cataract surgery removes all LFCs and the most part of the anterior lens capsule, followed by implantation of an intraocular lens within the rest of the capsular bag. Thereafter, LECs on the remaining anterior lens capsule divide and encroach on the posterior lens capsule, leading to opacification [159]. Depletion of MΦ positive for ED1, ED7 and ED8 ameliorates such LEC overgrowth [160]. These findings, together with the evidence for UV cataracts [161], suggest that inflammation causes cataractogenesis. Circulating autoantibodies against lens proteins are frequent in patients with senile cataracts or diabetic cataracts [162,163]. Glycated Cry and its autoantibody exist in sera of cataract patients [164], suggesting that leakage of Cry to the outside of the lens (e.g., from the degenerated lens capsule) results in autoantibody production. Sera from patients with senile cataracts or anti β-Cry antibody are cytotoxic to LECs [165]. Lens opacities are more prevalent in rabbits positive for antibodies raised against human lens proteins than antibody-negative rabbits [166], implying that some types of cataracts are an autoimmune disease. Autoimmunity against lens Cry may also mediate lens-induced uveitis, which involves cellular but

Implications for IR cataractogenesis Early onset cataracts vs late onset cataracts

PSC cataracts: LECs in the GZ of the lens epithelium around the equator divide [27]. Rodent cataracts occur after irradiation of the equatorial region [181], but not after irradiation with the GZ shielded [182–184]. Taken together, inhibition of LEC divisions prevents IR cataractogenesis in frogs and rats [185–187], indicating that dividing LECs are the relevant cells at risk of early onset PSC cataracts. In vivo excessive proliferation of rabbit LECs in the GZ within 21 days post IR occurs slightly at 125 [r] (roughly equals 1.25 Gy), became evident at 250 [r] and more manifested at higher dose (tested up to ~2000 [r]) [188]. In vitro excessive proliferation of human LECs is significant at ≥2 Gy [179]. These dose ranges passably resemble the acute threshold of 0.5–2 Gy for detectable lens opacities and 2–10 Gy for VIC that ICRP recommended for a few decades before 2011 [7,12,189]. Whereas complete loss of organelles during LFC differentiation is critical for lens transparency [190], excessive proliferation may cause meridional row disorganization (the known essential event associated with cataract severity) and force undifferentiated LECs to move posteriorly before organelle loss, which may eventuate in PSC opacification [27,191]. Early onset PSC cataracts may thus involve excessive LEC proliferation, for which a threshold sounds biologically plausible. Considering that the lens is a closed system, cells constituting opacities should not be limited to excessively proliferated cells, and may also include inactivated or dead cells (e.g., via premature senescence, apoptosis, necrosis, autophagy, and nonpermanent yet very long term cell cycle arrest). Such cells and progeny of irradiated cells may move posteriorly much slower than excessively proliferated cells, contributing to late onset PSC cataracts. If abnormal cells arising from

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damaged single cells form cataracts, then no cataract threshold may sound biologically plausible. A recent report highlights that a lens progenitor-like cell differentiated from human embryonic stem cells generates a lentoid body [192], warranting further studies to test if an irradiated single lens stem cell forms a cloudy lentoid body. Cortical cataracts: In senile cataracts, cortical cataracts are most common whereas PSC cataracts are least common. This raises the possibility that acceleration of age related changes underlies late onset IR cortical cataracts, which is discussed here from the viewpoint of NTEs. NTEs are effects arising in cells whose nucleus receives no direct IR traversals, and include bystander effects and genomic instability [193]. Bystander effects occur in nonirradiated bystander cells having received signals from irradiated cells, and the progeny of irradiated cells also cause bystander effects in nonirradiated cells [194]. Genomic instability occurs in the progeny of irradiated cells and in the progeny of bystander cells [194]. Such interrelation between bystander effects and genomic instability highlights that continuous spatiotemporal propagation of signals initially transmitted from irradiated cells may perpetuate IR effects in their neighborhood and progeny over time, leading to persistent NTEs [131]. Proposed NTE mechanisms involve GJIC and reactive oxygen/ nitrogen species (ROS/RNS), and persistent metabolic oxidative stress occurs in irradiated cells and nontargeted cells [195]. IR augments Cx43-mediated GJIC, and other environmental stimuli (e.g., heat stress and UV) also alter GJIC [196–198]. The nature of factors communicated through GJs remains unidentified, but one possible candidate would be long-lived radicals (LLRs) that persist even for a day causing mutation and transformation [199]. Nontargeted cells bear elevated LLR levels [200]. LLRs are considered as sulfinyl radicals [201], and glutathione radicals might be able to travel through lens Cx46 GJs [202]. Another candidate might be LTCC-mediated calcium waves [203], and oxidative stress due to elevated ROS/ RNS also increases lens Ca2+ via inactivation of Ca2+ ATPase [204,205]. Increased serum Ca2+ levels are associated with A-bomb PSC cataracts [87,206], though its association with the intracellular lens Ca2+ level is not known. Cry is evolutionally related to proteins involved in protection against stress [207]. IR (e.g., 1000–4000 Gy of γ-rays) and oxidative stress cause oxidation, nitration, isomerization and racemization of α-Cry [208,209], where αA-Cry is more radioresistant than αB-Cry [210]. IR (e.g., about 5–15 Gy of X- or γ-rays) also produces d-aspartic acids in the mouse lens [211]. Such changes due to oxidative and calcium metabolisms resulting from direct or indirect targeted effects and persistent NTEs may cause cataracts. Persistent NTEs underpin IR-induced chronic inflammation [212]. Reported transmissible NTE factors include Cox-2, colony stimulating factor 2 (CSF2), RNA-containing exosomes, soluble Fas ligand (FasL), interferon α inducible protein 27 (IFI27), interleukin 1α (IL1α), IL-1β, IL-6, IL-8, IL-33, monocyte chemoattractant protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2), MMP-9, regulated upon activation normal T-cell expressed and secreted (RANTES), secretory clusterin (sCLU), transforming growth factor β1 (TGFβ1), tumor necrosis factor α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), extracellular DNA fragments, nucleotides, ATP and other factors associated with the senescence-associated secretory phenotype [194,213–219]. Of these, IL1, IL6, IL8 and TNFα are proinflammatory cytokines, and the involvement of IL1, IL6 and TGFβ1 in cataractogenesis is known [220]. IR upregulates MMP-2 and MMP-9 in lens cells [221], and these two MMPs (especially MMP-9) mediate TGFβ1-induced cataractogenesis [222]. Inflammation is associated with A-bomb cataracts [87]. Thus, IR-induced inflammation may cause cataractogenesis. Nevertheless, contributions of IR-induced inflammation to IR cataractogenesis may be smaller than direct radiation effects to lens cell populations [223],

and the relative contribution of IR-induced inflammation to the overall radiation effects may be smaller in the lens than other tissues. This is because MΦ does not access inside the lens with the intact capsule, and because the eye including the lens is an immunologically privileged organ. Thus, long-term low-level chronic oxidative stress, chronic inflammation and disrupted calcium homeostasis may cause late onset IR cortical cataracts. Tumor related factors and DNA repair factors There is evidence that IR cataracts involve Atm, Rad9 and Brca1 in mice, and A-bomb cataracts may also involve ATM (see subsection ‘Cataractogenesis and DSB repair genes’). Although the information is limited, p53, p21Waf1/Cip1 and Pten also appear to participate in IR cataractogenesis [224]. Evidence is not available for the role of other tumor related factors or DNA repair factors discussed in the section ‘Role of DNA repair factors in cataractogenesis’. However, contribution of all these factors to IR cataracts is possible, because IR causes DSB, SSB, crosslinks and base lesions [225]. Nuclei of LECs are positive with 8-hydroxyguanosine (oxidative adduct) and XRCC1 after IR [226], suggestive of the ongoing XRCC1 mediated repair. NDRG2 overexpression sensitizes human LECs to oxidative stress [62], but IR-induced NDRG2 promotes tumor radioresistance [227]. Thus, it might be interesting to test the role of NDRG2 in IR cataracts. In mice, p53 prevents spontaneous PSC cataractogenesis by suppressing cellular proliferation and promoting cell death [27]. p53 controls LFC differentiation through regulation of two transcription factors (c-Maf and Prox-1) [228], and delays while p21Waf1/Cip1 drives spontaneous cataractogenesis in BubR1 progeroid mice [67]. Thus, it would be worth testing if enhancement of p53 function suppresses IR-induced excessive proliferation and early onset PSC cataracts. Consideration of mechanisms behind posterior LEC migration is also crucial. FGF2 and TGFβ induce LEC migration by activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway [229], and a gradient of concentration of FGF2, TGFβ and other growth factors has been proposed to play critical roles in determining LEC proliferation and posterior migration [230]. IR induces FGF2 in human LECs [231], and NTEs involve TGFβ (see subsection ‘Cortical cataracts’). Such IR-induced growth factors may promote posterior LEC migration leading to PSC cataractogenesis. An important albeit fully open question is why IR and UV have different impacts on cataract induction. PSC cataracts and cortical cataracts are the most common and the second most common IR cataracts, respectively. Conversely, PSC cataracts are least common, and cortical cataracts are most common in UV cataracts. UV not only generates SSB, CPDs, 6-4PP and other base lesions, but also produces DSB in a replication-dependent and -independent manner [232]. Elucidation of the role of DNA damage in different cataractogenic effects of IR and UV awaits further studies. The distant impact of partial irradiation within the lens Less irradiated cells coexist with more nonirradiated counterparts in a tissue exposed to a lower dose of higher-LET IR [233]. The possible distant impact of IR on cataractogenesis can be addressed by experiments with the partially shielded lens irradiation. Leinfelder and Riley reported in 1956 that, when a single quadrant of the rabbit lens is irradiated with ~30 Gy to which exposure of the entire lens causes a complete opacification, or even with its quadrupled dose (~120 Gy), only a partial opacity occurs in the irradiated quadrant [183]. A complete opacification does not occur in the irradiated two opposite quadrants each of which receives the quadrupled dose [183]. Worgul et al. [234] recently confirmed such protective effect of partial irradiation in rats, but found that partial irradiation with 10 mGy or 50 mGy creates vacuoles and discrete

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opacities in the nonirradiated portion of the partially irradiated lens more frequently than those in the nonirradiated lens or fully shielded lens. These findings suggest that communications between nonirradiated and irradiated compartments relieve and exacerbate cataractogenesis. However, incipient opacities in the partially irradiated lens do not progress to maturity [183], so that protective effects appear to outstrip damaging effects at the tissue level. It is also of interest to note that a series of studies with high dose partial irradiation experiments consistently reported no lenticular changes in the nonirradiated portion of the partially irradiated lens: for instance, Alter and Leinfelder wrote in 1953 that “unexposed quadrants remained clear and there is no general or diffuse effect” [182]. This raises the possibility that such damaging effect with a distant impact is a low dose phenomenon. Conclusions Cataracts are very common, but the lens does not develop tumors spontaneously, indicating that senescence outweighs tumorigenesis in the lens. The biological significance of opacification is unclear, but opacification itself may serve as an anti-carcinogenesis mechanism. In this respect, this analytical review paper has provided a first attempt to systematically discuss a link between cataractogenesis and carcinogenesis. It is now evident that cataractogenesis involves a variety of factors and processes of which associations with carcinogenesis are known. Involvement of tumor related factors in cataractogenesis is obvious (see section ‘Role of tumor related factors in cataractogenesis’, Table 1 and Fig. 1). Considering that many of such factors control various basic functions like proliferation and differentiation, its functional disruption is possible to contribute to cataractogenesis. However, the roles of tumor related factors are not simple, such that spontaneous cataractogenesis is not necessarily augmented by oncogenes nor attenuated by tumor suppressor genes. This necessitates more clarification, but p53 may be especially relevant to IR PSC cataracts. All available evidence illustrates that impaired DNA repair enhances spontaneous cataractogenesis, with the exception of one study reporting associations of XPD polymorphisms with a decreased cataract risk in Caucasians [111] (see section ‘Role of DNA repair factors in cataractogenesis’, Table 2 and Fig. 1). The lens cells communicate with one another through Cx GJs in cooperation with AQP water channels, and its abrogation facilitates spontaneous cataractogenesis (see section ‘Role of intercellular interactions in cataractogenesis’ and Fig. 1). Inflammation exacerbates spontaneous cataractogenesis, although the contribution of inflammation to the entire cataractogenesis processes may be minimal due to the ocular immune privilege (see section ‘Role of inflammation and other immune responses in cataractogenesis’ and Fig. 1). Such roles of DNA repair factors, intercellular interactions and inflammation in spontaneous cataractogenesis should have direct implications for IR cataractogenesis (see section ‘Implications for IR cataractogenesis’ and Fig. 2). In its latest recommendations, ICRP writes “among the most radiosensitive tissues in the body are ovary and testes, bone marrow and the lens of the eye” [235]. Such radiosensitivity of the lens may be attributable to cell death/inactivation, impaired differentiation (e.g., imperfect denucleation), and denaturation of lens proteins. Unlike cells in gonads and bone marrow, lens cells are not necessarily vulnerable to IR-induced cell killing or inactivation [179]. However, all dead/inactivated lens cells stay inside the lens, and thus should act as a source of light scattering. IR, steroids and diabetes mainly induce PSC cataracts, while UV mainly induces cortical cataracts, indicating that cataractogenesis dispenses with DNA damage. Nonetheless, involvement of DNA repair is obvious as aforediscussed, and high-LET IR more effectively induces cataracts than low-LET IR [131], suggesting that both DNA damage and repair play roles in IR cataracts. Haploinsufficiency of Atm, Rad9 and Brca1 for IR cataracts has important implications for genetic susceptibility,

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although further studies are warranted to determine whether such ATM haploinsufficiency results from attenuated kinase activity for DNA repair or other activities such as in regulating redox signaling, mitochondrial function and metabolic control [236]. Enhancement of p53 function may alleviate IR cataracts. Further studies are clearly encouraged to establish countermeasures to mitigate IR cataracts, and also essential for strengthening a scientific basis of the radiation protection system. We have postulated that whereas early onset cataracts occur with a threshold after acute exposure, late onset cataracts occur with no threshold regardless of the rate of dose delivery [180]. If this is true, then IR cataracts can be a tissue reaction as well as a stochastic effect. Conflict of interest The authors hereby declare no conflicts of interest. References [1] W. Rollins, Notes on x-light. The effect of x-light on the crystalline lens, Boston Med. Surg. J. 148 (1903) 364–365. [2] D.G. Cogan, S.F. Martin, S.J. Kimura, Atom bomb cataracts, Science 110 (1949) 654–655. [3] P.H. Abelson, P.G. Kruger, Cyclotron-induced radiation cataracts, Science 110 (1949) 655–657. [4] ICRP, International recommendations on radiological protection, Br. J. Radiol. 24 (1951) 46–53. Radiology 56 (1951) 431–439. (n.b., the same contents were published in two different journals). [5] ICRP, Recommendations of the International Commission on Radiological Protection, Br. J. Radiol. 28 (Suppl. 6) (1955) 1–92. [6] ICRP, ICRP Statement on tissue reactions/Early and late effects of radiation in normal tissues and organs – threshold doses for tissue reactions in a radiation protection context, Ann. ICRP 41 (2012) ICRP Publication 118. [7] N. Hamada, Y. Fujimichi, Classification of radiation effects for dose limitation purposes: history, current situation and future prospects, J. Radiat. Res. 55 (2014) 629–640. [8] N. Hamada, Y. Fujimichi, T. Iwasaki, N. Fujii, M. Furuhashi, E. Kubo, et al., Emerging issues in radiogenic cataracts and cardiovascular disease, J. Radiat. Res. 55 (2014) 831–846. [9] C.J. Martin, A 20 mSv dose limit for the eye: sense or no sense?, J. Radiol. Prot. 31 (2011) 385–387. [10] M.C. Thorne, Regulating exposure of the lens of the eye to ionising radiations, J. Radiol. Prot. 2 (2012) 147–154. [11] S. Bouffler, E. Ainsbury, P. Gilvin, J. Harrison, Radiation-induced cataracts: the Health Protection Agency’s response to the ICRP Statement on tissue reactions and recommendation on the dose limit for the eye lens, J. Radiol. Prot. 32 (2012) 479–488. [12] ICRP, 1990 recommendations of the International Commission on radiological protection, Ann. ICRP 21 (1991) ICRP Publication 60. [13] B. Emami, J. Lyman, A. Brown, L. Coia, M. Goitein, J.E. Munzenrider, et al., Tolerance of normal tissue to therapeutic irradiation, Int. J. Radiat. Oncol. Biol. Phys. 21 (1991) 109–122. [14] I.M. Osman, H. Abouzeid, A. Balmer, M.C. Gaillard, P. Othenin-Girard, A. Pica, et al., Modern cataract surgery for radiation-induced cataracts in retinoblastoma, Br. J. Ophthalmol. 95 (2011) 227–230. [15] F.A. Cucinotta, W. Schimmerling, J.W. Wilson, L.E. Peterson, G.D. Badhwar, P.B. Saganti, et al., Space radiation cancer risks and uncertainties for Mars missions, Radiat. Res. 156 (2001) 682–688. [16] D. Pascolini, S.P. Mariotti, Global estimates of visual impairment, Br. J. Ophthalmol. 96 (2012) (2010) 614–618. [17] D.C. Beebe, Maintaining transparency: a review of the developmental physiology and pathophysiology of two avascular tissues, Semin. Cell Dev. Biol. 19 (2008) 125–133. [18] U.P. Andley, Crystallins in the eye: function and pathology, Prog. Retin. Eye Res. 26 (2007) 78–98. [19] J. Graw, Mouse models of cataract, J. Genet. 88 (2009) 469–486. [20] T. Mochizuki, I. Masai, The lens equator: a platform for molecular machinery that regulates the switch from cell proliferation to differentiation in the vertebrate lens, Dev. Growth Differ. 56 (2014) 387–401. [21] B.P. Danysh, T.P. Patel, K.J. Czymmek, D.A. Edwards, L. Wang, J. Pande, et al., Characterizing molecular diffusion in the lens capsule, Matrix Biol. 29 (2010) 228–236. [22] R.C. Augusteyn, Growth of the human eye lens, Mol. Vis. 13 (2007) 252–257. [23] C.J. Zeiss, E.M. Johnson, R.R. Dubielzig, Feline intraocular tumors may arise from transformation of lens epithelium, Vet. Pathol. 40 (2003) 355–362. [24] K.A. Mahon, A.B. Chepelinsky, J.S. Khillan, P.A. Overbeek, J. Piatigorsky, H. Westphal, Oncogenesis of the lens in transgenic mice, Science 235 (1987) 1622–1628. [25] A.E. Griep, R. Herber, S. Jeon, J.K. Lohse, R.R. Dubielzig, P.F. Lambert, Tumorigenicity by human papillomavirus type 16 E6 and E7 in transgenic mice

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Please cite this article in press as: Nobuyuki Hamada, Yuki Fujimichi, Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.02.017