Transcription-coupled repair and premature ageing

Mutation Research 577 (2005) 179–194

Review

Transcription-coupled repair and premature ageing J.O. Andressoo, J.H.J. Hoeijmakers ∗ MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus Medical Center, P.O. Box 1738, 3000DR Rotterdam, The Netherlands Received 11 March 2005; received in revised form 31 March 2005; accepted 2 April 2005

Abstract During the past decades, several cellular pathways have been discovered to be connected with the ageing process. These pathways, which either suppress or enhance the ageing process, include regulation of the insulin/growth hormone axis, pathways involved with caloric restriction, ROS metabolism and DNA repair. In this review, we will provide a comprehensive overview of cancer and/or accelerated ageing pathologies associated with defects in the multi-step nucleotide excision repair pathway. Moreover, we will discuss evidence suggesting that there is a causative link between transcription-coupled repair and ageing. Published by Elsevier B.V. Keywords: Biology of ageing; NER-associated disease; Transcription-coupled repair

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleotide excision repair (NER) associated disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Cockayne syndrome (CS) and COFS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Trichothiodystrophy (TTD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Xeroderma pigmentosum (XP) and XP with DeSanctis-Cacchione syndrome (XP-DSC) . . . . . . . . . . . . . . . . . 2.4. XP combined with CS (XPCS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. XP combined with TTD (XPTTD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What defines the specificity of NER-associated disease? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Neuronal loss in XP-DSC versus CS, COFS and TTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Loss of subcutaneous fat tissue in NER disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The enigmatic differences between clinical phenotypes of NER disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. XP and XP-DSC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. CS and TTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corresponding author. E-mail address: [email protected] (J.H.J. Hoeijmakers).

0027-5107/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.mrfmmm.2005.04.004

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4.3. TTD and the TFIIH complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. XPCS and XPTTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. COFS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Why do TCR-deficient syndromes exhibit only segmental premature ageing? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In the human population, the biological significance of functional DNA damage repair is apparent from the severe clinical features seen in individuals with DNA repair-related disorders. These patients display a common phenotype of segmental premature ageing (progeria), cancer predisposition, or both. An incomplete list of such syndromes includes Li-Fraumeni syndrome, ataxia telangiectasia (AT), Fanconi Anemia (FA), Nijmegen Breakage syndrome (NBS), Bloom syndrome (BL), Werner syndrome (WR), hereditary nonpolyposis colon cancer (HNPCC), cerebro-oculofacio-skeletal syndrome (COFS), xeroderma pigmentosum (XP), XP with DeSanctis-Cacchione syndrome (XP-DSC), Cockayne syndrome (CS), and trichothiodystrophy (TTD). The molecular cause of the above human diseases is malfunctioning in sensing and/or repairing DNA damage [1–7]. The latter five syndromes—COFS, XP, XP-DSC, CS and TTD can be caused by mutations in proteins involved in nucleotide excision repair (NER) [8]. Intriguingly, all five disorders (and combinations XPTTD and XPCS) can be triggered by mutations in one NER gene—XPD [2,8–10]. Also other genes such as XPB and XPG are linked with multiple conditions. 2. Nucleotide excision repair (NER) associated disorders Mutations in the highly conserved NER pathway can lead to autosomal recessive XP, XP-DSC, CS, TTD, COFS and combinations like XPTTD and XPCS [2,8–10]. Although NER involves at least 30 proteins in a multi-step repair reaction, mutations in 11 NER proteins have so far been found to be associated with human pathology. It is to be expected that patients will be identified for many of the other factors. Table 1

189 189 190 190 190 191 191

presents the genes involved in the various syndromes. In addition, the less severe UVS (UV-sensitive) syndrome has been identified due to mutations in CSB, or in another yet unidentified gene. While CS and TTD share many neurodevelopmental features, XP is mostly associated with a very strong sun-induced skin cancer susceptibility not observed in either TTD or CS. In about 20% of XP cases, accelerated neuronal degeneration occurs (XP with DeSanctis-Cacchione syndrome, XP-DSC), resulting in, e.g., dementia, memory loss or intellectual impairment [11]. The nature of neuropathy in XP-DSC, although reminiscent of premature brain ageing, is quite distinct from what is observed in CS and TTD. CNS anomalies in CS and TTD are mostly associated with demyelination (white matter degeneration), while neuronal loss (grey matter degeneration) is the primary cause of XP with DeSanctis-Cacchione syndrome [11–14]. Yet, similar to CS and TTD patients, XP patients with neuronal manifestations often display developmental delay, gait disturbance and deafness, underlying a link between neuronal failure and the Table 1 The main NER-associated human diseases and causative genes XP

XP-DSC

CS

TTD

XPCS

XP/TTD

COFS

XPA2 XPC2 XPD6 XPE1 XPF2 XPG3 XPV1 XPE1

XPA2 XPD6

CSA1 CSB2

XPB2 TTDA1 XPD6

XPB2 XPD6 XPG3

XPD6

CSB2 XPG3 XPD6

Number in upper case behind each gene indicates the number of different syndromes in which the given gene has been implicated thus far. In the case of the same gene being implicated in multiple conditions such as for XPD, each disorder is associated with syndromespecific causative mutant alleles [32,35,40–42] (N. Jaspers, personal communication).

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above developmental features. Unlike in CS and TTD patients, defects in neuronal migration and innervation in COFS (CNS anomalies include both white and grey matter) starts already during development in utero [2]. Rapid postnatal degeneration of both the glial and neuronal compartment in COFS and severe failure to thrive leads to death during the first few years of life [2,15]. Notably, the severe form of CS (CS type II), COFS and infantile XPCS complex are one of the most severe dwarfing illnesses known [16]. In view of the severe nature and very early onset of these conditions it is likely that many cases go undiagnosed. To understand the mechanisms of NER-related disease, one has to be aware of disease etiology associated with each disorder. In the following sections, NER-associated pathology is discussed in a greater detail. 2.1. Cockayne syndrome (CS) and COFS CS is a rare, autosomal recessive disorder, resulting in progressive postnatal growth failure (cachexia), neurological dysfunction and symptoms reminiscent of segmental accelerated ageing (progeria) resulting in early death on average ∼12.5 years of age for the reported cases (which may bias towards the more severe forms of the disease) [13,17]. In general, older CS patients have a very characteristic appearance, including overall “aged” look, large ears and nose, sunken eyes, unsteady, wide based gait and thin appearance due to progressive loss of subcutaneous fat tissue [13]. Normal in utero development of a CS patient is followed by profound growth failure, which generally begins within the first year of life. Soon after birth, the brain of CS patients fails to grow and remains extraordinarily small throughout their lives, but remarkably, is not grossly malformed. CS patient’s cognition and social behavior are less impaired than one would predict from diminutive brain size. The above findings and the almost exclusive postnatal timing of growth impairment in CNS make it unlikely that the cause of the extreme microcephaly (small head and brain) of CS results from prenatal premature curtailment of neurogenesis, disordered neuronal migration, or grossly aberrant connectivity. Postnatal interference with the proliferation, branching, and deployment of neuronal processes seems more plausible [16]. The postnatal increase in oxidative DNA damage load [18–20] may explain the almost exclusive postnatal onset of CS.

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The earliest common neurological symptom in CS is delayed psychomotor development. The progressive gait disorder is a manifestation of the combination of spasticity of the legs, (mainly cerebellar) ataxia, tremors, contractors of the hips, knees and ankles often accompanied by kyphosis of the vertebral column [13]. All CS patients are mentally retarded, yet, this feature varies from mild to severe retardation. Despite progressive cognitive, sensory, and communicative difficulties, CS patients are described as happy, social, interactive or friendly [13]. It is important to note that the early onset of cataracts, neurological dysfunctioning and microcephaly is associated with poor prognosis and survival. To date, among ∼200 CS cases [16] no patients have been reported with normal neuronal functioning but severe other CS symptoms, arguing, that progressive neuronal failure may be among the primary causes of the systemic pathological outcome. This notion is supported by post-mortem pathological findings, which in general reveal the lack of overall chronic tissue degeneration or cell death (necrosis or apoptosis) in any organ system except for the central nervous system (CNS) and peripheral nervous system (PNS) [13]. Due to progressive neuronal decline and cachexia, patients gradually lose ability to move and to make contact with the outside world, they become passive and fail to feed actively. Tube feeding in general provides temporary alleviation (J.O.A., personal communication with CS society “Care and Share”). Progressive failure to thrive and neurodysfunction is often followed by increased susceptibility to infectious diseases such as pneumonia/respiratory infections, which are often reported as an ultimate cause of death. Perhaps secondary to cachexia, renal or hepatic failure has also been noted as a cause of death in several cases [13]. Laboratory tests of hematologic and immunologic parameters as well as thyroid, adrenal, and hepatic function do not show significant abnormalities in CS. Glucose tolerance tests, basal or stimulated growth hormone levels, and responses to insulin, arginine, and glucagon have not revealed the causes of the dramatic dwarfing and cachexia [16], nor did growth hormone therapy result in significant progress in growth [13]. Most frequent radiological findings include intracranial calcifications, sclerotic epiphyses most prominent in the fingers and pelvic and vertebral anomalies includ-

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ing kyphosis. Osteoporosis was registered in a few patients pointing to premature ageing of the skeleton. It should be noted though that the above data in the clinical reports are often from different stages of the disease. That might explain some at first glance conflicting observations. For example, the notion that bone age in 10 CS patients was found to be advanced, in five normal and in six delayed may well reflect late, medium and early stages of CS, respectively, where delayed bone age may mirror an overall developmental delay prior the onset of premature ageing in CS. On the other hand, visual or auditory evoked potentials in CS were always found abnormal. This is reminiscent of profound cataracts, retinal degeneration and deafness observed in CS. Nerve conduction velocity analysis (EMG/NCV) is impaired in most patients. Muscle biopsies have shown variable changes, none thought to be primary. Analysis of CNS by MRI or CT scans has revealed increased ventricular size and/or cerebellar and cerebral atrophy and/or calcifications in basal ganglia and elsewhere [13]. Calcifications as well as appearance of neurofibrillary tangles reported in some cases of CS [21], are features of normal ageing, but appear early in CS. Most of the brain anomalies in CS are associated with white matter, or so-called glial compartment. The glial cells, more specifically oligodendrocytes are the cells, which isolate axons of the neurons (grey matter) by wrapping them into a myelin sheet. Proper myelinization is required for high velocity conduction as well as neuronal survival. It has been proposed, that demyelinization is the primary neuronal defect in CS [12]. Nevertheless, recent post-mortem examinations of CS patients have revealed neuronal loss within several neuronal populations, such as those in the Meynert nucleus, putamen/caudate, thalamus, globus pallidus, dentate nucleus, granule cells and Purkinje cells [22]. Except in the cerebellum, these changes may be secondary because they were found adjacent to the demyelinated lesions. Thus the CNS symptoms in CS are complex and in addition to white matter may well comprise grey matter. Many CS patients display hypogonadism, such as undescended testis. It is tempting to speculate that under-developed gonadal axis may contribute to neuronal loss as gonadal steroid hormones are implicated in survival of several neuronal populations, such as hippocampal neurons, also implicated in CS [23,24]. Astrocytes, the second of the

three glial populations in the CNS, are also affected in CS. They are found pleomorphic, a few are multinucleated, and many are bizarre and irregularly shaped with swollen, lobulated, hyperchromatic nuclei [16]. Interestingly, similar bizarre astrocytes and Purkinje cell loss is found in ataxia-telangiectasia (AT) patients [25]. AT-mutated (ATM) protein is a key regulator of signaling downstream of DNA damage, particularly DNA breaks. Thus, the cellular signaling as a response to defective DNA repair in CS, or defective signaling on its own in AT can lead to similar pathology. COFS can be also regarded as a severe form of CS. Nevertheless, COFS-syndrome eye defects (i.e., microcornea with optic atrophy) are more severe than those usually associated with CS (i.e., pigmentary retinopathy [2]). Symptoms include reduced birth weight, early microcephaly with subsequent brain atrophy, reduced white matter, patchy grey matter, hypotonia, deep-set eyes and cataracts. Movement is markedly decreased, joint contractures common. Like in case of CS patients (and XP patients with DeSanctis-Cacchione syndrome, see below) a frequent cause of death is pneumonia/respiratory infections. 2.2. Trichothiodystrophy (TTD) The clinical manifestation of TTD patients, including developmental delay, cachexia, neurodemyelination, cerebellar ataxia, mental retardation, microcephaly, sensorineural deafness and cause of death, is largely overlapping with that of CS [14]. Distinguishing hallmark of TTD from CS is scaling skin (ichthyosis), and brittle hair and nails. The latter is caused by greatly reduced content of cysteine-rich matrix proteins in the hair-shafts, which cross link the keratin filaments and provide physical strength to the hair. This is the last step in the terminal differentiation of the hair and this TTD feature can therefore be regarded as inability to complete the differentiation program, leaving the hair fragile and vulnerable to physical breakdown [26,27]. Pathological changes in the epidermis include hyperkeratosis (thickened keratin layer responsible for the scaling skin) and acanthosis (thickening of epidermal layer) [14]. Also these features are due to inability to complete the terminal differentiation program, resulting in unfinished skin and nails in which keratin filament cross-linking is deficient.

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2.3. Xeroderma pigmentosum (XP) and XP with DeSanctis-Cacchione syndrome (XP-DSC) Unlike CS, TTD and COFS, XP is always associated with clinical and cellular sensitivity to ultraviolet radiation and defective repair of UV-induced DNA lesions. To date ∼1000 XP patients have been described in the clinical literature. First symptoms of sun sensitivity in XP become evident at an average age of 2 years, when intense freckling and/or sunburn is first noted. XP patients display a more than 1000-fold elevated risk to develop sun-induced malignant skin neoplasms such as squamous cell carcinomas (SCC) and basal cell carcinomas (BCC). Yet, the frequency of metastasis appears to be quite low (5 out of 112 XP patients with SSC). Interestingly, a comparatively low 5% of XP patients are reported to develop melanomas. While 97% of SCC and BCC appear on sun-exposed areas such as face, head or neck, only 65% of melanomas were associated with this area, indicating that induction of a melanoma involves more complex and probably systemic factors. Among ocular tissues, the eyelids, conjunctiva and cornea receive substantial amounts of UV radiation and subsequently are strongly affected in XP patients. Anomalies of the eyelid include sunburn, atrophy of the skin, loss of lashes or even the whole eyelid [11]. Corneal abnormalities include corneal clouding and/or vascularization. Neoplasms of the eye are exclusively associated with conjunctiva, eyelid and/or cornea whereas SCC is the most frequently occurring neoplasm. Neurological abnormalities are reported in about 20% of XP patients (XP with DeSanctis-Cacchione syndrome (XP-DSC)). Although extraneurologic features such as number and aggressiveness of skin tumors between XP and XP-DSC patients appear similar, the average onset of sun sensitivity for XP-DSC is 6 months versus 2 years for classical XP [11]. Eighty percent of XP-DSC patients are mentally retarded, whereas less than a quarter of the patients display concomitant microcephaly, growth retardation, gait anomalies such as spasticity and ataxia; and sensorineural deafness, all of which have a progressive character [11,12,22]. As in case of CS, COFS and TTD, the earlier the onset of neuronal features in XP-DSC, the more pronounced the degree of retardation of growth and sexual development [11,16,22] again strongly suggesting a link between DNA repair, neuronal deployment and sur-

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vival, and somatic development and maintenance. The above notion is supported by studies in model organisms, such as the fruit fly (Drosophila melanogaster). When oxidative damage load in motor neurons is lowered by over-expressing the ROS scavenger enzyme superoxide dismutase 1 (SOD1), the transgenic flies live 40% longer than wt [28]. What is the difference between CS and XP-DSC? XP-DSC patients do not develop CS-specific features such as demyelination of CNS and PNS, retinal degeneration and calcifications of the basal ganglia and other brain areas. Instead, XP-DSC patients exhibit degeneration of specific populations of neurons on top of suninduced skin freckling and/or skin cancer. In general, CS is associated with more severe symptoms, including microcephaly and cachexia. The most predominant difference seems to lie in the primary cell-type affected in the CNS. Except for the neuronal loss in the cerebellum, CS-specific demyelination in other areas of CNS leaves the neurons relatively intact. In XP-DSC myelin is not affected, yet besides neuronal death in the cerebellum (resulting in CS-like ataxia) several other neuronal populations die in the other areas of the CNS, such as in the cortex and substantia nigra, resulting in progressive intellectual deterioration, dementia and gait anomalies [12,16,22]. Why the CS defect primarily affects the myelinating cells (oligodendrocytes) and XP-DSC defect the neuronal cells, and how this results in often overlapping phenotype remains to be elucidated. Since neuronal conductivity is a function of proper myelination and neurons and not oligodendrocytes establish the cellular connections both within CNS and with the soma, it is tempting to speculate that at least a subset of overlapping features of CS and severe XP-DSC are caused by a defect in neuronal functioning. 2.4. XP combined with CS (XPCS) In rare cases (n = 9) a combined XPCS pathology has been reported [25]. There is a remarkable degree of clinical variation in XPCS. The three patients with XPCS carrying a point mutation in the essential XPB gene (see Table 1) had a much less severe CS phenotype with survival between the third and the fifth decade of life compared to those in groups XP-D and XP-G. Two patients in XP group D and the remaining four in XP-G all displayed very severe disease [25]. The phenotype of patient XPCS2 (XPD-G602D) at 9

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Fig. 1. XPCS patient XP20BE (XPG-XPCS). Progressive pathology of Cockayne syndrome features. Note the normal fullness of the face at 4 and 18 months of age and the typical CS appearance with deep-set eyes, prominent ears and profound cachexia at the age of 6 years. XP pigmentary changes and CS-specific wrinkling of the skin of the hand showing signs of premature ageing. Death occurred at the age of 6.2 years. Reprinted from [56] with permission from the European Paediatric Neurology Society.

years of age included classical features of both XP and CS. He had a CS-characteristic facies associated with acquired microcephaly, severe mental retardation and progressive dementia, gait abnormalities and cachectic dwarfism, retinal degeneration, demyelinating neuropathy, spasticity, reduced nerve conduction of the leg, cryptorchidism (a form of under-developed testis) and hyperactive reflexes in the lower extremities. He died at the age of 13. XP pigmentary changes were evident as early as 2 weeks of age, the first skin tumor was noted at 2.5 years of age [25,29,30]. The other XPD-XPCS patient and all XPG-XPCS patients displayed even more severe pathology and died at age of 7 months, 1.7, 2, 6.2 and 6.5 years, respectively [25]. Unfortunately, an overall chronological pathology record for most of the above patients is missing. Neuropathology of patient XP20BE (XPG-XPCS, see Fig. 1) has been documented the best and will be herein described briefly. Electromyogram (EMG) analysis suggested primary neuropathic but notably also primary myopathic features, suggesting that muscle cell degeneration can also occur independently of axonal loss in PNS of XPCS. Patient XP20BE died at the age of 6.2 years because of profound cachexia and pneumonia. His brain weight was 350 g, while the expected brain weight of a child at that age is 1200 g. Most of the pathological findings in the brain were typical for CS.

In the midbrain the substantia nigra had focal neuronal loss—a feature characteristic for XP-DSC. Neuronal loss was noted also in hippocampus and certain brainstem nuclei. The cerebellum displayed typical CS features, including neuronal loss in Purkinje and internal granular layers. Taken together, loss of myelinated fibers and neurons was profound with resultant dementia, ataxia and notably dysmetria (overshooting of the aimed position of the limbs) [25]. Is neuronal cell death primary or secondary to demyelination? Most of the demyelinating lesions are found outside of the cerebellum. Purkinje cells are innervated mostly by granular cells within the cerebellum and not by neurons from other brain areas. Thus, the loss of Purkinje cells (and granular cells) is likely the primary neuronal defect and not secondary to an oligodendrocyte defect. Taken together, the extreme CNS pathology seen in XPCS and CS likely results from the primary DNA repair defect in oligodendrocytes, some neuronal populations and to some extent, a combination of these cell-types. 2.5. XP combined with TTD (XPTTD) Recently, two patients have been identified with a combined form of XPTTD [9]. The follow-up of these patients is relatively short and disease etiology of this condition is still largely unexplored. However, the mere existence of these patients underscores the parallel of

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Table 2 Clinical symptoms of NER disorders Clinical symptoms

XP

XP-DSC

CS

TTD

XPCS

XP/TTD

COFS

UV sensitivity Increased freckling Skin cancer Cachectic dwarfism Microcephaly Progressive cognitive impairment Sensorineural deafness Eye abnormalities Skeletal abnormalities Spasticity Ataxia Axonal neuropathy Demyelinating neuropathy Myopathy Brain calcification Hypogonadism Brittle hair and nails Hyperkeratosis Progeria

++ ++ ++ − − − − − − − − − − − − − − − −

++ ++ ++ + + + + + ? + + ++ − − − + − − +/−

++a − − ++ ++ ++ ++ ++ + ++ ++ +/− ++ − ++ ++ − − ++

++a − − ++ ++ ++ ++ ++ + ++ ++ ? ++ − ++ ++ ++ ++ ++

++ ++ ++ ++ ++ ++ ++ ++ + ++ ++ + ++ +/− ++ ++ − − ++

++ ++ + + ? ++ − ? ? ? − ? ? − ? ? + + ?

? ? ? +++ +++ +++ +++ +++ ++ +++ +++ ? ? ? +++ ? ? ? ?

a ∼50%

of patients display this feature. Assembled from recent literature reports [40,45,47].

TTD with CS and highlights that the clinical heterogeneity associated with mutations in the XPD gene. A summary of pathological features of NER disorders is provided in Table 2.

3. What defines the specificity of NER-associated disease? NER is a complex, multi-step process that removes bulky, helix-distorting lesions and requires the concerted action of at least 30 proteins, many of which have additional functions outside of the pure NER context. Two major pathways can be distinguished: global genome NER (GG-NER) and transcription-coupled repair (TC-NER). These pathways utilize different modes of damage recognition, but then feed into the same core reaction. As explained in Fig. 3 in GG-NER, the XPC/hHR23B complex is the primary lesion detector, triggering the recruitment of the rest of the NER machinery [31]. For some lesions, such as UV-induced CPD’s XPC needs the assistance of the XPE/UV-DDB complex [32]. In the TC-NER pathway pioneered by the laboratory of Phil Hanawalt [33,34], blockage of the elongating RNA-PolII is believed to initiate the

repair, a process which requires the CSB and CSA proteins [35,36] as schematically depicted in Fig. 3. Recent evidence suggests that certain NER proteins are not only involved in removing transcription-blocking bulky adducts but may be required for transcriptioncoupled repair (TCR) of any lesion that arrests the elongating RNA polymerase complex. This is of major biological importance and is discussed in a greater detail in the last section of this review. TC-NER and GG-NER proceed similarly by recruiting TFIIH. The XPD and XPB helicase components of the 10 subunit TFIIH complex partially melt the suspected region. At this stage the XPC complex is presumably released and the stalled polymerase is thought to be displaced or removed, perhaps with the help of the CSB, CSA and XPG proteins. This makes the lesions accessible to the remainder of the NER team. Binding of subsequent factors such as XPA and the single-stranded DNA binding RPA trimer lead to full opening of a stretch of ∼30 bp around the DNA lesion. XPA is important for verification and demarcation of the damage and consequent proper orientation of the NER complex. Next, the structure-specific endonuclease XPG performs incision 3 from the lesion at the transition of ss to ds DNA, followed by 5 cleavage by the XPF/ERCC1 complex. NER is completed by gap-filling of the excised patch

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by DNA polymerases (such as DNA-Pol␧ or -␦) and the resulting nick is ligated, likely by DNA ligase I [1,35]. In vivo the entire GG-NER reaction takes ∼4 min as determined by photobleaching methods of NER factors tagged in living cells with green-fluorescent proteins [37]. Several recent lines of evidence point to a major involvement of the ubiquitin system in both the GG-NER and the TCR reaction [38,39]. Finally, it should be noted that the GG-NER system is relatively well understood due to the establishment of an in vitro reaction [40,41] and reconstitution using recombinant factors [42]. However, all efforts to set up an equivalent cell-free assay for the presumably more complex TC-NER mechanism have met with little success. Consequently, the initial steps in this reaction are not known. It is intriguing that although NER is a ubiquitous repair mechanism auditing the genome in each cell of our body removing dozens if not hundreds of different types of lesions, associated NER disorders display a surprising variety of pathologies, ranging from mild UV sensitivity to >1000 times elevated cancer risk (XP) to accelerated ageing (CS, TTD) and combinations of these. From this pathological diversity it is clear that not all the tissues and cell-types are affected in a similar manner. Different inactivating mutations in NER proteins may affect the repair of distinct lesion types, the spectrum of which likely depends on a metabolic rate and type and differentiation stage of a given cell. For example, the increased skin cancer in XP is attributable to UV-induced enhanced mutation rates in the basal layer of the skin. The latter process is linked with defects in GG-NER, leading to elevated mutagenesis in the entire genome. Defects in TC-NER, on the other hand, have not been associated with significantly enhanced mutagenesis as this repair system mainly deals with one strand and only a very small fraction of the genome. In contrast, TC-NER may be more relevant for promoting cell survival after DNA damage induction, as it ensures the continued use of damaged genes for transcription. This is supported by a series of findings that demonstrate a tight link between defects in TC-NER and induction of apoptosis [43–45]. Why on the other hand XP-DSC is associated with the loss of neurons, while oligodendrocyte degeneration is one of the most dominant pathologies in CS is largely unknown. Nevertheless, those distinct pathologies may serve as important clues for disclos-

ing the primary mechanisms in each disorder and this will be discussed in more detail below. 3.1. Neuronal loss in XP-DSC versus CS, COFS and TTD First, why do mutations in NER proteins specifically affect cells of neuronal origin? Several lines of evidence suggest neuronal type of cells to utilize NER in a highly specific manner. First, neurons differentiated in vitro appear significantly more UV-sensitive than, e.g., fibroblasts or HeLa cells [46,47]. It has been shown, that GG-NER activity declines dramatically during neuronal differentiation in vitro [48] and thus, e.g., cannot support DNA repair when TCR activity is hampered by a CS-type of mutation. The latter has been shown to render a number of cells hypersensitive to the cytotoxic effects of transcription-blocking lesions [43–45]. From clinical studies it is known, that demyelination (white matter loss) is a late response to CNS gamma irradiation [49]. Pathological findings in the brains of chemotherapeutically-treated or gamma-irradiated patients (and laboratory animals) reveal neuronal and glial degeneration [12] (D. Dickson, personal communication) and post-mortem comparison of brains from the above patients with those from CS patients and normal ageing individuals revealed a remarkable degree of pathological similarity (D. Dickson, personal communication). Taken together these observations suggest that neurons and glia are hypersensitive to DNA damage of both exogenous (e.g., gamma rays) and endogenous (reactive metabolites, e.g., ROS) origin. ROS most likely are produced as a function of metabolic rate. The latter may explain the specific loss of Purkinje neurons in XP-DSC, CS, and TTD alike as those cells are believed to be metabolically and transcriptionally among the most active cell-types in the brain [12]. What underlies the difference between neuronal loss in XP-DSC and oligodendrocyte deficit in CS, TTD and COFS? Clearly, there are qualitative differences between specific repair pathways in XP-DSC and CS, TTD and COFS. While 100% of XP-DSC patients are UV-sensitive, enabling their assignment to a certain XP complementation group by monitoring UV-induced NER in cellular assays, a substantial fraction (∼50%) of CS, TTD and COFS patients are not and thus the genes affected have remained unknown. A likely expla-

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nation here is that mutations in non-UV sensitive CS, TTD and COFS patients specifically affect the broader TCR pathway but not (as discussed below) the GG(and perhaps TC-) NER function of the given protein. Because systematic efforts to sequence NER proteins in those patients have not yet been performed and nonNER TCR capacity is difficult to measure, the latter explanation remains hypothetical. Since cell-type, differentiation status [47,50] and metabolic type and rate likely determine both the lesion spectrum and repair activity in a given cell, it is tempting to speculate that neuronal loss in XP-DSC is caused by TC-NER deficit of bulky adducts, combined with a GG-NER defect whereas oligodendrocyte loss in TTD, CS and perhaps COFS is related to inability to remove the presumably broader spectrum of TCR targets from transcribed genes. Schematically, this concept can be set forward in the following scenario: “Due to differences in metabolism, different cell-types have different DNA lesion spectra, which will lead to different demands on DNA repair and damage response systems. Thus a specific mutation affecting a given repair protein/pathway induces a specific phenotype.” The above scenario may not only explain the differences in neuronal phenotype but may also provide a plausible explanation for other premature ageing features found to differ between these syndromes. Thus, e.g., COFS may result from an extreme deficit in TCR. An intriguing clue relevant in this context came from recent observations from Phil Hanawalt and coworkers who found that in differentiated cells such as neurons, TC-NER acts in a different mode, so-called differentiation associated repair or DAR. DAR preferentially repairs both, transcribed and non-transcribed strands of genes [47,48]. Future studies addressing specific effects of XP-DSC, CS, XPCS and TTD type of mutations on this repair trail are therefore of great interest. The role of GG-NER in neuronal phenotypes seems relatively limited because (i) GG-NER is downregulated upon cellular differentiation [47,48] and (ii) patients lacking XPC, the primary damage sensor in GG-NER, in general do not develop neuropathies, in contrast to XP and CS complementation groups in which the TC-NER pathway is significantly affected. Vulnerability of neuronal tissue to endogenous damage is also supported by studies suggesting the involvement of ROS in the onset of Parkinson’s disease, dementia and Alzheimer’s disease (reviewed in

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[51,52]) as well as by studies with non-homologous end-joining (NHEJ) defective (e.g., XRCC4 knockout) mice, which display embryonic lethality likely due to massive neuronal apoptosis [53]. 3.2. Loss of subcutaneous fat tissue in NER disorders Besides neuropathies, a subset of XP-DSC, and all CS, COFS and TTD patients gradually loose subcutaneous fat tissue. This is one of the clinically most important aspects of the disease as it largely determines the overall health status of patients. Like in other differentiating cells, GG-NER in adipocytes is downregulated [47]. Whether DAR occurs also in those cells still needs to be determined. Nevertheless, unlike most of neuronal cell-types, adipocytes are constantly turned over and thus the defect may either lie in mature adipocytes, the adipocyte stem-cell compartment or both. The third possibility for the onset of cachexia, i.e., defects in neuroendocrine regulation of fat metabolism may be set aside as thus far no consistent evidence pointing to defects in this axis has been established in patients. Recently, embryonic stem cells were found to be more vulnerable to a wide range of genotoxic stresses than fibroblasts or keratinocytes [50], suggesting that stem cells, in order to avoid damage accumulation and subsequent tissue malfunctioning and/or carcinogenesis have a lower apoptosis threshold than other cell-types. In concordance with that notion, various CS mouse models display time-dependent loss of tubular germinal epithelium in the testis (J.O. Andressoo et al., submitted). Although hypogonadism is also a prominent feature in CS, TTD and COFS to our knowledge, histological examinations have not been performed and thus human-mouse comparisons of that tissue type cannot be made.

4. The enigmatic differences between clinical phenotypes of NER disorders The large differences in disease etiology of XPA (completely defective in both GG-NER and TC-NER) and, e.g., CSB and CSA (defective in NER limited to TC-NER) patients led to the hypothesis, that mutations in NER proteins resulting in symptoms different from XP such as those observed in CS, TTD, XPCS,

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XP/TTD and COFS might be due to functions of these proteins outside the context of the classical NER pathway or of the NER spectrum of lesions. Two parallel mutually non-exclusive hypotheses have been considered. First, the “transcription syndrome” hypothesis, based on TFIIH dual functionality in NER and transcription. Mutations in these proteins may, besides NER, also affect the basal and/or activated transcription [54–57]. Due to the exclusive association of mutations in TFIIH subunits with TTD, this condition has been suggested to result at least in part from defects in basal transcription [27,54,57]. Indeed, the latter hypothesis was supported by the finding that mRNA levels of proteins responsible for the lower degree of cross-linking of keratin filaments in the skin of TTD mice are reduced, thus explaining the TTD hallmarks of brittle hair and nails and scaly skin [27]. This feature appears to be independent of the extent of the repair defect in both TTD patients and in single TTD and XPA/TTD double mutant mice and therefore is separate from the repair function of TFIIH or the NER status as such. The interpretation that TTD brittle hair is due to a basal transcription problem is also entirely consistent with the observed instability of TFIIH in TTD fibroblasts [58–60] and TTD MEFs and with the identification of an unusual TTD patient with more pronounced TTD features in episodes with high fever, which turned out to be due to a ts instability of TFIIH caused by the specific XPDTTD mutation [60]. Secondly, the transcription-coupled repair (TCR) hypothesis, based on the notion that CS, and XPCS cells from patients and mice are slightly, but significantly more sensitive to oxidative agents [61,62]. Since most oxidative lesions are normally repaired by BER and not by NER, the existence of a general TCR pathway was suggested, in which proteins involved in CS are required to repair all types of transcription-blocking lesions, i.e., not only transcription-stalling NER, but also BER, and perhaps other transcription-blocking injuries [63–65]. In this role CSB may closely monitor elongating RNA polymerases for normal progression of the transcription process, explaining its close link with the elongation machinery [37,66,67]. A further level of complexity was added by the report that CSB protein may be involved in RNA-PolI transcription [66]. Which of those many processes primarily affects the outcome of a specific disease feature? Do TTD, CS and XPCS and perhaps COFS embody the same or differ-

ent causes of neurodevelopmental pathology such as accelerated segmental ageing? Although the problem seems intricate, recent data including the genetic analysis of several patient-born mouse models (discussed in a greater detail below) have provided some important clues. 4.1. XP and XP-DSC XP and XP-DSC are triggered by a classical NER defect (as defined by cellular sensitivity to UV irradiation) and are thus defective in removing bulky, helixdistorting adducts. The mechanism of skin cancer in XP and XP-DSC alike has been convincingly attributed to the GG-NER defect by multiple independent studies (reviewed in [8,68]) (Fig. 3). This is consistent with the high cancer predisposition exhibited by XPC patients and the XPC mouse mutant. Whether or not neuronal cells are affected (the discriminating feature between XP and XP-DSC) may depend on the effect the given mutation delivers on the as yet poorly understood DAR pathway, possibly via its effect on the TC-NER process. 4.2. CS and TTD Neurodevelopmental features in CS and TTD, which are distinct from those in XP-DCS, are triggered by a deficit in the same basic mechanism: most likely TCR. The involvement of a common mechanism is based on the following notions: (i) in the majority of human inborn dwarfing disorders the onset is prenatal (i.e., developmental), whereas both CS as well as TTD have an almost exclusive postnatal onset; (ii) except for the TTD-specific brittle hair and nails (addressed in greater detail above) TTD and CS pathology shares a remarkable similarity. Moreover, when totally NER-defective Xpa−/− mice were crossed to either Csa−/−, Csb−/−, XPCS (XPDG602D ) or TTD (XPDR722W ) mice strikingly the same set of segmental ageing features were dramatically exacerbated. All the double mutants showed largely overlapping features of progressive postnatal cachexia, kyphosis, loss of subcutaneous fat tissue, cerebellar ataxia, spasticity of movements, failure to thrive and shared the maximum life span of ∼3 weeks [65,69,70] (J.O. Andressoo et al., submitted). In addition, mice double mutant for Xpc and Csb or Csa exhibited similar pathology and life span [70] (I. van der Pluijm et al., in preparation),

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confirming that the observed acceleration of ageing was due to endogenous DNA damage and not due to some unknown function of XPA. A quite similar phenotype was also reported for Xpg-deficient mice [71], while a mild mutation in XPG required additional XPA inactivation to result in an analogous pathology [72]. Likely, CSA, CSB, XPD, XPB and XPG proteins are involved in the same reaction thereby enabling onset of overlapping pathology when defective. We propose this reaction to be TCR, thus the repair trail which contributes to the removal of a wide range of transcription-interfering lesions, including those normally genome-wide removed by specified repair pathways such as BER, GG-NER or perhaps also homologous recombination. (Figs. 2 and 3). Whether the TCR machinery only facilitates back-tracking or removal of the blocked RNA-PolII from the lesion followed by the recruitment of specific repair pathways or whether TCR also includes repair by the core NER reaction for all blocking lesions is currently unknown. 4.3. TTD and the TFIIH complex As discussed, the TTD-specific features of brittle hair, nails and scaling skin are due to instability of the TFIIH complex. The specific mutations in the XPB, XPD and TTDA (p8) subunits render the entire complex less stable. This interferes with completion of the terminal differentiation program of keratinocytes, because in the absence of de novo synthesis, TFIIH is exhausted by the time the last genes need to be transcribed and therefore the proteins that crosslink the keratin filaments are underexpressed leaving the hair and nails brittle and the skin scaly. In conclusion, while the common deficit in DNA repair, likely within the TCR (or DAR) trail underlies the overlapping mainly premature ageing features in CS, and TTD, the additional specific features of TTD are due to the additional role of the given proteins outside their function in repair, notably basal transcription.

Fig. 2. Schematic outline of the GG-NER and TCR reaction. After the damage recognition step by hHR23B/XPC or elongating RNAPol II, respectively, GG-NER and TCR pathways likely utilize the common core NER reaction, which involves recruitment of TFIIH and XPA followed by melting of the DNA around the lesion. Following DNA melting excision of the damaged strand is performed by structure-specific endonucleases XPG at 3 and XPF/ERCC1 at 5 side of the lesion, respectively; and gap-filling and ligation by the replication machinery. The role of proteins in NER indicated with a question mark is uncertain. 1 UV-DDB (XPE) complex is required for initiation of XPC dependent repair of specific lesions (e.g., UVinduced CPD’s). 2 Genetic evidence suggests that in TCR TFIIH and XPG alongside with CS proteins may be involved in early steps, such as removal or back-tracking of blocked RNA-PolII from the lesion (indicated by dotted arrows). Whether within the TCR context the majority of lesions are repaired by core NER reaction or by specific repair trails (e.g., BER, HR) is currently unknown.

4.4. XPCS and XPTTD XPCS and XPTTD are due to a combined GG-NER and TCR defect. The existence of a combination of XP and CS or TTD, each of which are extremely rare on their own, indicates that these types of deficits are not mutually exclusive, instead are likely to be mech-

anistically linked. In terms of the known functional engagements of the gene products concerned the combination can be best explained by the simultaneous impairment of the global genome NER pathway leading to the XP features and TCR triggering the severe neurodevelopmental symptoms of CS as well as the CS

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component in TTD. In fact, the combined GG-NER and TCR defects could synergize as the GG-NER defect will lead to a constitutive higher level of damage in the genome enlarging the problems for the defective TCR machinery and causing more genes to experience transcription insufficiency. Thus, variation in the extent of the GG-NER and TCR deficiencies may explain the large variation in severity of the clinical symptoms observed between different XPCS patients. This is consistent with the severe premature ageing phenotypes expressed by double XPA/CSB mutant mice (and other double mutant mice showing the same phenotype, see above). Moreover, a number of XPD-XPCS cells were recently found to induce untargeted nicks in the DNA in response to UV irradiation [73], a mechanism which on top of the GG-NER defect likely enhances mutagenesis and consequently carcinogenesis. The two reported XP/TTD cases on other hand, may be explained at least in part by co-dominant effects of differentially point-mutated XPD alleles present in those patients [9]. A recent discovery that both XPD alleles, even when one of the two alleles causes embryonic lethality in a homozygous state, can be important in determining the disease outcome (J.O. Andressoo et al., submitted) adds ground to this interpretation and invites for studies dissecting effects of each allele product for other genes as well. 4.5. COFS COFS can also be regarded as a severe form of CS. It has been found to be caused by one point mutation in XPD [2]. Also a mutation in CSB has been noted to give rise to COFS. Intriguingly, this mutation appeared to cause a remarkably mild C-terminal truncation of the CSB protein [74], whereas in many CS patients much more severe mutations have been observed in the CSB gene. In striking contrast, a patient with the even milder UV-sensitive syndrome was recently found to be caused by an even more severe CSB mutation deleting almost the entire CSB protein [75]. The inverse relation between the clinical severity of CSB patients and the molecular severity of the mutated gene product argues in favor of a model in which it may be better to have no CSB than to have a protein that functions partially. It would be reasonable to presume that TCR defect in COFS is more pronounced than in CS or TTD. One interpretation is that the reaction trig-

gered by a mutant CSB leads to an intermediate that is more difficult to resolve than when the reaction was not initiated at all. Unfortunately, despite years of efforts by multiple laboratories, direct measurement of TCR capacity independent of TC-NER remains controversial and attempts to reconstitute this enigmatic reaction in vitro have to date been unsuccessful. Clearly, more research focusing on TCR and its specific form—DAR is required to understand the molecular basis of NERassociated diverse pathology.

5. Why do TCR-deficient syndromes exhibit only segmental premature ageing? Why are accelerated ageing features observed in several DNA repair mutants segmental, i.e., affecting some organs and tissues more than others and in this regard only in part mimick normal ageing? The most logical explanation is that organs and tissues differ in metabolism and exposure. This will result in organ/tissue specific differences in frequency and spectra of lesions and consequently organ/tissue specific dependence on the corresponding repair response and tolerance systems. In addition as discussed before the nature, efficiency, capacity and fidelity of the genome care-taking apparatus may vary in different tissues/organs and stages of development. The same may hold for scavenging systems. As a consequence defects or natural variation in one pathway may translate in an ageing problem in only a subset of organs and tissues. In view of the high specificity of DNA repair mechanisms in parallel with the different nature of DNA repair inactivating mutations which range from full, to partial inactivation and their multi-functional nature, it is expected, rather than surprising, that defects in various DNA repair proteins and pathways result in segmental, not full reconstitution of ageing.

6. Concluding remarks The intricacies of the GG-NER, TC-NER and presumably the broader TCR reaction combined with the occurrence of functions beyond repair of several of the NER factors and global genome repair defects translates into a complex and highly pleiotropic set of syndromes. However, by careful analysis of patients and

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mouse mutants we can come to the following simplifications. A defect in the global genome subpathway of NER as observed in XPC patients causes the cutaneous features of XP with the high incidence of skin cancer in the UV-exposed parts of the skin. When in addition the TC-NER pathway is affected as in the case of XPA the additional feature of accelerated neurodegeneration may be occurring as seen in extreme extent in the DeSanctis-Cacchione form of XP. The CS features including those apparent in TTD may be the consequence of a defect in the broader TCR system, with TTD having on top of this the TFIIH instability leading to the typical brittle (unfinished) hair, nails and skin. Interestingly, for the severity of the CS symptoms there seems to be an inverse correlation with the severity of the defect at the molecular level: seemingly mild CSB mutations induce the extremely severe form of CS called COFS, whereas a virtually complete inactivation of the gene goes along with the mild UV-sensitive syndrome [75]. This discloses some of the mechanistic intricacies that still need to be resolved. The problems caused by defective TCR can be further aggravated by a combination with a deficiency of the GG-NER subpathway, presumably because this increases the overall damage load. This may explain the very severe phenotype exhibited by some XPCS patients. Altogether this highlights the importance of the process that keeps our transcription going despite the continuous induction of DNA lesions, transcription-coupled repair, a system that was discovered and pioneered by Phil Hanawalt.

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Special thanks to N.G.J. Jaspers, J. Mitchell, G. Garinis and S. Bergink for helpful discussions. This work was financially supported by the Netherlands Organization for Scientific Research (NWO) through the foundation of the Research Institute Diseases of the Elderly, as well as grants from the NIH (1PO1 AG17242-02), NIEHS (1UO1 ES011044), EC (QRTL1999-02002), and the Dutch Cancer Society (EUR 992004).

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