Interactions of high mobility group box protein 1 (HMGB1) with nucleic acids: Implications in DNA repair and immune responses

DNA Repair 83 (2019) 102701

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Review article

Interactions of high mobility group box protein 1 (HMGB1) with nucleic acids: Implications in DNA repair and immune responses Pooja Mandke, Karen M. Vasquez

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Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX, 78723, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: High mobility group box 1 protein (HMGB1) DNA damage DNA repair V(D)J recombination Autoimmunity

High mobility group box protein 1 (HMGB1) is a highly versatile, abundant, and ubiquitously expressed, nonhistone chromosomal protein, which belongs to the HMGB family of proteins. These proteins form an integral part of the architectural protein repertoire to support chromatin structure in the nucleus. In the nucleus, the role of HMGB1 is attributed to its ability to bind to undamaged DNA, damaged DNA, and alternative (i.e. non-B) DNA structures with high affinity and subsequently induce bending of the DNA substrates. Due to its binding to DNA, HMGB1 has been implicated in critical biological processes, such as DNA transcription, replication, repair, and recombination. In addition to its intracellular functions, HMGB1 can also be released in the extracellular space where it elicits immunological responses. HMGB1 associates with many different molecules, including DNA, RNA, proteins, and lipopolysaccharides to modulate a variety of processes in both DNA metabolism and in innate immunity. In this review, we will focus on the implications of the interactions of HMGB1 with nucleic acids in DNA repair and immune responses. We report on the roles of HMGB1 in nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and DNA double-strand break repair (DSBR). We also report on its roles in immune responses via its potential effects on antigen receptor diversity generation [V(D)J recombination] and interactions with foreign and self-nucleic acids. HMGB1 expression is altered in a variety of cancers and immunological disorders. However, due to the diversity and complexity of the biological processes influenced by HMGB1 (and its family members), a detailed understanding of the intracellular and extracellular roles of HMGB1 in DNA damage repair and immune responses is warranted to ensure the development of effective HMGB1-related therapies.

1. Introduction Eukaryotic DNA is highly condensed and packed into the nucleus to perform its critical functions. This compaction is achieved by a group of architectural proteins, predominantly the histones. Apart from the histones, there exists a group of non-histone architectural proteins, the high mobility group (HMG) superfamily of proteins that bind to DNA in a non-sequence specific manner. These proteins derive their name from their characteristic high mobility in polyacrylamide gels [1]. The HMG superfamily is divided into three families based on their DNA binding domains: the AT hook domain containing HMGA; the HMG box containing HMGB; and the nucleosomal binding domain containing HMGN proteins [2,3]. The DNA structure-dependent interactions of these proteins are highly dynamic and affect both DNA and chromatin structures, thereby impacting processes such as DNA replication, transcription, and DNA repair [4,5]. The HMGB proteins are highly

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abundant; for example, estimates of ˜1 molecule of HMGB1 per ten nucleosomes in mammalian nuclei have been reported [4]. These proteins bind the minor groove of DNA and have a characteristic domain structure consisting of a Box A N-terminal domain, a Box B central domain, and an acidic C-terminal domain (Fig. 1). It has been shown that the Box A domain binds DNA [6], the Box B domain binds and facilitates bending of DNA [7], and the C-terminal tail plays a regulatory role in the DNA binding and bending properties of the HMGB proteins [8,9]. The HMGB family is comprised of four members HMGB1-HMGB4, which share over 80% sequence homology; while HMGB1-3 contain all three domains, HMGB4 lacks the acidic C-terminal tail [2,10]. These proteins bind distorted DNA, e.g., bulges, four-way junctions, and DNA adducts with high affinity, and as a consequence of their binding and bending activities they are known to affect chromatin structure and transcription of genes [5]. In this review, we will focus on the HMGB1

Corresponding author. E-mail address: [email protected] (K.M. Vasquez).

https://doi.org/10.1016/j.dnarep.2019.102701 Received 2 July 2019; Received in revised form 9 September 2019; Accepted 9 September 2019 Available online 16 September 2019 1568-7864/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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photolesions) in mouse embryonic fibroblasts (MEFs), survival was reduced in the absence of HMGB1, and importantly, DNA damage-induced mutagenesis was increased in the absence of HMGB1. In addition, it was found that HMGB1 facilitated chromatin modifications following DNA damage in these cells [30]. In further support of a role for HMGB1 in recognizing NER substrates, we found that HMGB1 interacted with the NER damage recognition proteins, XPC-RAD23B and RPA in vitro, and facilitated their interactions on TFO-ICLs [14]. The effect of HMGB1 on ICL processing was similar in human cells depleted in HMGB1 using siRNA as that found in MEFs knocked down for HMGB1, where HMGB1 was involved in the error-free processing of ICLs independent of the p53 status of the cells. This function, in part, was attributed to its potential role in forming a topology favorable for the recognition and repair of DNA lesions [18]. Using a combination of studies in MEFs and human cells we have shown that HMGB1 acted as an NER co-factor by facilitating NER-associated processing of DNA damage [31]. Interestingly, findings in support of a ‘repair shielding’ effect of HMGB1 have been reported, where in vitro analyses have shown an inhibitory role of HMGB1 in the repair of cisplatin-DNA lesions [32,33], also reviewed in [31]. A recent study was undertaken by YuseinMyashkova et al. (2016) to assess the role of HMGB1 in repairing cisplatin-induced DNA damage in mouse fibroblasts. Host cell reactivation assays were performed using a plasmid containing a cisplatin adduct, and three different HMGB1 constructs (WT, acetylation-deficient mutant HMGB1 K2A, or a C-terminal-deficient mutant). Using these constructs, the authors found that the expression of WT HMGB1 and the HMGB1 K2A mutant resulted in decreased repair of cisplatin-damaged DNA at 16 h, but not at 36 h post-transfection, whereas the C-terminaldeficient mutant showed a negligible decrease in the repair of cisplatindamaged DNA over time. Interestingly, the depletion of HMGB1 increased the repair of cisplatin-damaged DNA 16 h after transfection [34]. Hence, in their assay HMGB1 was found to inhibit the repair of cisplatin-induced DNA damage at an early time point, but not at a later time point. Thus, the differences in the roles of HMGB1 in DNA repair as seen in the host cell reactivation (HCR) assay could be attributed to the time point at which the assay was performed. In addition to the studies mentioned above, experiments to correlate cisplatin sensitivity and HMGB1 levels in cells to explain the repair shielding role, have yielded inconsistent results. A study by Wei et al. (2003) revealed that HMGB1 knockout MEFs and the parental MEFs did not show a substantial difference in sensitivity to cisplatin [35]. However, He et al. (2000) showed that in the breast cancer cell line MCF-7, increased levels of HMGB1 increased the sensitivity of cells to cisplatin [36]. This apparent disparity in the response of cells to cisplatin treatment and its relation to HMGB1 led some groups to hypothesize the involvement of additional factors in governing sensitivity of cells to cisplatin in the presence of HMGB1. For instance, the redox state of HMGB1 may alter the repair of cisplatin; HMGB1 has a characteristic domain structure with a total of three cysteine residues being present across the different domains. Hence, HMGB1 can exist in a reduced form, an oxidized/sulphonyl form or a disulfide-modified form via formation of intramolecular disulfide bonds between the C23 and C45 residues [37] (Fig. 2). The cisplatin-DNA 1,2-d(GpG) intrastrand crosslink and HMGB1 interaction is thought to occur via two of these cysteines, C23 and C45, located in the A domain of HMGB1 [13]. A study was undertaken by Park et al. (2011) that showed that the redox potential of the Box A domain of HMGB1 was within the range of the intracellular redox potential [24]. In addition, in vitro analysis by Wang et al. (2013) indicated that a disulfide bond formed between these cysteines under oxidizing conditions led to a reduced capacity of HMGB1 to bind to cisplatin-modified DNA [25]. Together, these results implied that a considerable proportion of HMGB1 present within the cell would be in an oxidized form, thereby affecting its ability to interact with the cisplatin-DNA adducts [24]. Hence, the differences in the functions of HMGB1 could be

Fig. 1. Schematic of HMGB1 protein. The HMGB1 protein has two positively charged domains; BOX A and BOX B, and a negatively charged acidic C-terminal tail. The two domains along with the C-terminal tail play a role in the binding and bending of DNA.

protein. HMGB1 has been reported to be involved in several biological processes in the nucleus, such as transcription, replication, repair, and recombination, and several reviews have been published that highlight these roles of HMGB1 [2,11,12]. The importance of HMGB1 in DNA damage repair gained attention following its observed high affinity binding to chemotherapy-induced DNA adducts, such as cisplatin-DNA lesions [13] and psoralen plus UVA (PUVA)-induced DNA interstrand crosslinks [14,15]. Interestingly, HMGB1 not only facilitates DNA damage recognition but can also influence DNA repair efficiency via direct interactions with DNA repair enzymes. Owing to its ability to bind distorted/damaged DNA structures, HMGB1 has now been implicated in four DNA repair pathways; NER, BER, MMR, and DSBR [16–18]. In the nucleus, HMGB1 is also identified as a key player in V(D)J recombination, thereby influencing the production of both B cell and T cell antigen receptor repertoire [19]. Apart from its function in the nucleus, HMGB1 can be passively secreted from necrotic cells or actively secreted from immune cells, such as activated macrophages [20,21], and in this capacity, can function as a mediator of inflammation. Though DNA in the nucleus was the first molecule identified to interact with HMGB1, it is now appreciated that HMGB1 can interact with multiple other molecules, including RNA, proteins, lipopolysaccharides (LPS), nucleosomes, and several cell surface receptors, subsequently activating downstream immune responses [22]. HMGB1 can also undergo many post-translational modifications, which can impact its functional outcomes. For example, HMGB1 can be acetylated, which can affect its subcellular localization [23], and HMGB1 may be oxidized to generate HMGB1 molecules with different redox states that can impact its ability to modulate both DNA repair and inflammatory responses [24–26]. Hence, HMGB1 is a highly versatile protein, and depending on its location viz. nuclear, cytoplasm, or the extracellular compartment, this protein can carry out various biological functions [27]. It can function in multiple complexes with other cytokines, DNA, RNA, proteins, and/ or LPS. In this review, we will focus on the interactions of HMGB1 with DNA and its functions in DNA damage repair and immune responses.

2. Roles of HMGB1 in DNA repair 2.1. HMGB1 and nucleotide excision repair (NER) HMGB1 has a high affinity for DNA lesions that are substrates for the NER mechanism, such as UV-induced DNA lesions and cisplatininduced DNA damage. Hence, a large body of work has focused on investigating the roles of HMGB1 in the processing and repair of these lesions. For example, we have investigated the function of HMGB1 in processing a specific type of DNA damage that is processed by NER in which we utilize a triplex-forming oligonucleotide (TFO) to create a site-specific psoralen DNA interstrand crosslink (ICL). These TFO-ICLs have been shown to be bound by the NER proteins XPA and RPA with high affinity and specificity [28], and processed by NER in an errorgenerating fashion [29]. We have shown that HMGB1 recognized and bound TFO-ICLs cooperatively with the XPA-RPA complex [15]. Further analysis identified a role for HMGB1 in enhancing error-free repair of DNA damage in mammalian cells. Upon treatment with DNA damaging agents (PUVA to induce ICLs, or UVC irradiation to induce DNA 2

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As HMGB1 was found to bind flap-containing BER intermediates, inhibit SN BER, and stimulate APE activity, a role for HMGB1 in another sub-pathway of BER, long-patch BER (LP BER), was hypothesized. In LP BER, pol β strand displacement synthesis generates a flap that is removed by flap endonuclease 1 (FEN1) [17,39]. To investigate the role (s) of HMGB1 in LP BER, model flapped intermediates were used to evaluate FEN1-mediated cleavage of the substrates in the presence of HMGB1. In this context FEN1 cleavage activity was found to be stimulated in the presence of HMGB1. Co-immunoprecipitation experiments using MEF extracts, as well as purified proteins, revealed that this effect may be due to a direct physical interaction of FEN1 with HMGB1 [38]. These experiments also identified interactions between HMGB1, APE, and pol β. Interestingly, in addition to enhancing BER activities on DNA substrates, Balliano et al. (2017) demonstrated that HMGB1 could stimulate the activity of pol β on nucleosomal substrates [40]. In the context of disease, it has been demonstrated that repair of oxidative DNA damage within hairpin-forming CAG repeats can lead to repeat expansion, which is implicated in several neurological disorders, including Huntington’s disease [41–43]. Further, the aforementioned role of HMGB1 coupled with its ability to stabilize hairpin loops formed in the context of repeat sequences could potentially implicate FEN1 and HMGB1 in diseases of triplet-repeat expansion [44]. Indeed, in vitro experiments by Liu et al. (2009 and 2010) demonstrated that HMGB1 led to CAG repeat expansion. This could potentially be attributed to the role of HMGB1 in stimulating the enzymatic activity of APE1 to create single-strand breaks and/or the activity of FEN1 in generating DNA nicks [17,41].

Fig. 2. HMGB1 modified forms. A) HMGB1 oxidized: HMGB1 has three cysteine residues, two C23 and C45 in the BOX A domain and one C106 in the BOX B domain. B) HMGB1 disulfide modified: an intermolecular disulfide bond can be formed between C23 and C45 of HMGB1, while C106 is in the reduced form.

attributed to the type of cell, the redox environment present, and the residues of HMGB1 interacting with the damaged DNA. Additionally, post-translational modifications that may alter the role of HMGB1 in the repair of DNA lesions include those that have been shown to affect the localization of HMGB1 and its ability to bind and bend the DNA [23]. For example, lysine and serine residues of HMGB1 can be acetylated and phosphorylated, respectively, and consequently the binding affinities of these HMGB1 isoforms can be regulated by these modifications [23]. To summarize, the existing literature on the roles of HMGB1 in NERassociated repair has been contradictory, where results in support of both its ‘repair enhancing’ as well as ‘repair shielding’ role have been reported. The effects of HMGB1 on NER-associated processing of DNA damage are complex and results in this regard need careful interpretation. For example, DNA damage processing by HMGB1 may be impacted by a variety of experimental conditions, including the types of DNA damaging agents used and the assays employed. Further, the concentration of HMGB1 may have an impact on its function in DNA repair (reviewed in [31]). In addition to these factors, the cell types used, the experimental time points selected, the redox potential of the cell types and of HMGB1, and post-translational modifications of HMGB1 may impact DNA damage processing, particularly for the cisplatin-DNA adduct. Hence, these variations in the assays used need to be considered to understand the roles of HMGB1 in NER.

2.3. HMGB1 and mismatch repair (MMR) Using MMR reconstitution assays, Yuan et al. (2004) found that HMGB1 played a role in the initial damage recognition steps in MMR via binding of MLH1 and MSH2 [45]. Further studies by Zhang et al. (2005) revealed that exonuclease 1 (EXO1)-catalyzed DNA excision was facilitated by the coordinated action of HMGB1 with RPA. In addition, the activity of RPA could be replaced by HMGB1 in a reconstituted MMR system [46]. However, Genschel and Modrich (2009) using mouse embryonic fibroblast extracts with and without HMGB1, suggested that this protein was not essential for MMR in cell extracts [16]. Hence further studies are warranted to evaluate the role of HMGB1 in the MMR mechanism. 2.4. HMGB1 and DNA double-strand break (DSB) repair Potential roles for HMGB1 in DSB repair have been reviewed in [31]. Importantly, HMGB1 may contribute to radio-resistance in certain types of cancer cells, in part due to its involvement in DSB repair mechanisms. For example, a study by Shrivastava et al. (2016) to ascertain the role of intracellular HMGB1 in radio-resistance in bladder cancer found that the resistance was associated with increased levels of HMGB1 in various urothelial cell lines, and that HMGB1 knockdown increased the radiation response in these cells [47]. Further, HMGB1 knockdown resulted in higher levels of DNA damage, as assessed by increased gamma-H2AX levels in bladder cancer cells after radiation treatment. This was also corroborated by increased levels of tail moments in an alkaline comet assay in the HMGB1-depleted bladder cancer cells treated with radiation. These results suggested that perhaps HMGB1 played a role in radio-resistance in bladder cancer cells via its role in promoting DSB repair [47]. Interestingly, Ueda et al.. (2002) indicated that HMGB1 may also enhance integration of plasmid DNA into genomic DNA of mammalian cells upon transfection, which may be a result of non-homologous illegitimate recombination [48].

2.2. HMGB1 and base excision repair (BER) The first evidence of the participation of HMGB1 in the base excision repair (BER) mechanism was provided by Prasad et al. (2007), in which HMGB1 was shown to bind to a BER intermediate, a 5′-dRP flapped, single-nucleotide gapped substrate [38]. Interestingly, the authors found that HMGB1 possessed a weak 5ʹ-deoxyribose phosphate (5ʹ-dRP) lyase activity on this BER intermediate. Moreover, the 5′-dRP lyase activity of DNA polymerase beta (pol β) was inhibited in the presence of HMGB1, as was single-nucleotide BER (SN BER). Thus, the authors suggested that HMGB1 may compete with pol β for binding the 5ʹ-dRP group, resulting in the inhibition of SN BER. Because HMGB1 was found to bind BER intermediates containing apurinic/apyrimidinic (AP) sites, they next determined whether HMGB1 impacted the strand excision activity of the BER enzyme apurinic/apyrimidinic endonuclease (APE), and found that HMGB1 stimulated APE activity by > 10-fold.

2.5. HMGB1 and chromatin in DNA repair The repair of different types of DNA lesions takes place via repair 3

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Fig. 4. Dynamics of interactions of the acidic C-terminal tail of HMGB1 with Box A and Box B, and linker histone H1. The C-terminal tail of HMGB1 binds to the DNA-binding domains of HMGB1, restricting their interaction with DNA. However, the acidic tail of HMGB1 can interact with the basic tail of histone H1, thereby disrupting its interaction with the DNA-binding domains of HMGB1. This interaction can therefore lower the affinity of H1 for DNA and it can be displaced from the DNA by HMGB1, thereby facilitating binding of HMGB1 to DNA.

these regions [52]. In contrast, the bends introduced by binding of HMGB1 destabilizes the nucleosome and increases access to regions of DNA by promoting binding of chromatin remodeling proteins, such as ACF (ATP utilizing chromatin assembly and remodeling factor)/CHRAC (chromatin assembly complex), which induce sliding of nucleosomes [53]. This dynamic placement of either H1 or HMGB1 is thought to involve interactions between these two proteins (Fig. 4). Cato et al. (2008), using NMR spectroscopy proposed that the basic C-terminal domain of histone H1 interacts with the acidic tail of HMGB1, interfering with the HMGB1 tails and the HMGB1 DNA-binding domains, perhaps promoting the interactions of HMGB1 with DNA. As a result of this, the affinity of H1 for DNA maybe lowered and hence it can be displaced from the DNA by HMGB1 [54]. Another possible mechanism was demonstrated by Polanska et al. (2014), wherein they showed that the redox state of HMGB1 can not only affect its ability to bind and bend DNA, but also its ability to interact with histone H1. While the oxidized form of HMGB1 displayed a limited ability to displace H1 from DNA, the reduced form could displace H1 from the DNA efficiently. Hence the redox state of HMGB1 could affect chromatin stabilization, and consequently gene transcription [55]. In addition, Stros et al. (2015) found that DNA bending by HMGB1 in vitro could be inhibited by H1 and was impacted by the redox state of HMGB1 and/or the presence of its acidic C-terminal tail [56]. Apart from its interaction with histone H1, HMGB1 has also been shown to interact with histone H3 in a similar fashion involving the tails of the two proteins and subsequent enhancement of interactions of HMGB1 with nucleosomes [57]. An increase in accessibility to chromatin can potentially influence transcriptional activation of genes. In the context of HMGB1 it does so by bringing the transcription factors (e.g. p53) to their respective DNA binding sites [58,59]. Upon facilitating this interaction, HMGB1 is thought to dissociate from the complex, thereby leaving behind a stable DNA-protein complex. In the context of DNA repair, the most well studied example is the interaction of the tumor suppressor p53 with its cognate DNA binding site in the presence of HMGB1. The interactions of p53 with linear DNA are often weak; however, binding of HMGB1 to linear DNA was shown to bend the DNA, which facilitated p53 binding [5]. In contrast Das et al. (2001), using electrophoretic mobility-shift (EMSA) assays, have suggested that HMGB1 functioned as a transcriptional repressor when it formed a complex with the TATA-binding

Fig. 3. HMGB1-mediated modulation of DNA repair and chromatin remodeling. Upon DNA damage, distortions are caused due to formation of DNA lesions. Further DNA distortions are introduced upon binding of HMGB1 to these lesions. HMGB1 can then interact with different DNA repair proteins and chromatin remodeling factors, which favors the repair of damaged DNA. Figure reused from Ref. [25]. S.S. Lange, D.L. Mitchell, K.M. Vasquez, High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage, Proc. Natl. Acad. Sci. U. S. A., 105 (2008) 10320-10325. (Copyright (2008) National Academy of Sciences, U. S. A.).

pathways mentioned in the previous sections, which take place in the context of chromatin in cells, and include three important steps in repair: access to damage in the context of chromatin, repair of the damage in the context of chromatin, and restoration of the chromatin [49]. The extent of the involvement of HMGB1 in these steps has been reviewed in [31]; and see (Fig. 3). The effects of HMGB1 in DNA repair can also be attributed to its effect on chromatin structure, and consequently gene transcription during repair of damaged DNA. The interactions of HMGB1 with DNA are transient and occur in a non-sequence specific manner. The transient nature of these interactions allows HMGB1 to scan for binding sites in the nucleus in an efficient manner [50]. In addition to the transient interactions, the non-sequence specific interactions of HMGB1 with DNA ensure that the binding sites are not occupied by HMGB1 itself. This may allow HMGB1 to assist other proteins in binding to their cognate sites, thereby aiding in different cellular functions [51]. Accessibility of the chromatin is essential for DNA metabolic processes, and since histone H1 and HMGB1 are reported to occupy similar positions in the nucleosome, the dynamics of their interactions are important in determining accessibility of the chromatin. HMGB1 and histone H1 (H1) have been reported to compete both in the linker region as well as the entry/exit points of nucleosomes [2]. The functional consequence of this competition is that in presence of H1, the nucleosomes are stabilized by restricting the access of transcription factors to 4

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bend was predicted at the nonamer-spacer junction where HMGB1 was thought to engage with the phosphate backbone. Another bend was predicted at the location where RAG is thought to introduce distortion in the DNA upon binding, which creates a favorable structure for HMGB1 binding viz. the heptamer-coding flank junction. Additionally, a bend in the heptamer-spacer junction where the RAG-DNA interaction and the HMGB1 interaction have been detected in the 23RSS was predicted. Lastly, the center of the spacer region in the 23RSS complex where HMGB1 was observed to bind displayed a significant level of bending. The same group also revealed some differences in the architecture of the 12RSS complex after binding of the RAG-HMGB1 complex [69]. The implication of this observation was that differences in the HMGB1-dependent bending of the 23RSS spacer would not only allow for efficient binding of the heptamer and nonamer by RAG, but would potentially afford the RAG proteins the ability to distinguish between the 12RSS and the 23RSS complexes, perhaps assisting in the enforcement of the 12/23 rule for efficient V(D)J recombination. Lovely et al. (2015) used a tethered particle motion assay to observe the dynamics of V(D)J recombination at the single molecule level, and found that the binding of the RAG proteins to the RSS sequences was increased in the presence of HMGB1 [70]. In support of the need for a bent DNA conformation, using in vitro DNA binding and cleavage assays, Dai et al. (2005) demonstrated that either of the two box domains of HMGB1 could facilitate cleavage of naked DNA via the formation of the RAG1/2-HMGB-RSS complex. However, on nucleosome substrates in the context of chromatin both box domains of HMGB1 were essential for RAG1/2-mediated cleavage. They also showed that a bent DNA conformation was important for binding of HMGB1 to facilitate the downstream nicking of DNA followed by the formation of a hairpin structure. The need for a bent DNA structure was further supported by the observation of the requirement of the Phe38 residue in the A domain of HMGB1 (this residue is known to facilitate binding of HMGB1 to kinked DNA) to assist with the RAG1/ 2-RSS binding [71]. Previous work by Aidinis et al. (1999) had indicated that RAG1/2 could promote bending of the RSS sequence without the involvement of HMGB1 [67]. Hence, the authors hypothesized that HMGB1 could play role in stabilizing the RAG1/2mediated bent DNA structures, thereby assisting in the formation of DNA-protein complexes on the RSS sequences [71]. In general, V(D)J recombination is a highly regulated and accurate process in which the RSS sequences are the canonical targets for the RAG proteins. However, in certain cancers, such as leukemia and lymphoma, illegitimate activity of the RAG proteins has been linked to chromosomal abnormality [72]. Using in vitro plasmid-based assays, Zhang et al. (2009) identified a novel breakpoint sequence, bps6197, which was a substrate for the RAG proteins and lacked the canonical heptamer sequence (5′−CCTGACG-3′) adjacent to the breakpoint. Interestingly, a nonamer sequence, similar to the 23RSS was identified 30 nucleotides from the breakpoint site. Further biochemical analyses indicated that the standard nick-hairpin mechanism was involved in the cleavage of the bps6197 sequence by the RAG proteins. This novel site was found to be functionally similar to the 23RSS site and formed stable RAG-DNA complexes in vitro, comparable to the canonical 23RSS site. This cleavage not only required HMGB1 but also in vitro studies indicated that HMGB1 displayed a preferential binding to the bps6197 sequence. This preferential binding could, in part, be due to the presence of an inverted-repeat sequence adjacent to bsp6197, which may form a structural distortion (e.g. a hairpin or cruciform DNA structure), a preferred binding substrate of HMGB1 [73,74]. This indicated that HMGB1 not only participated in canonical V(D)J recombination, but under some circumstances may facilitate recombination at cryptic sites. Hence, a further understanding of this mechanism is essential due to its implications in disease etiology [62]. To further understand the role(s) of HMGB1 in V(D)J recombination, Little et al. (2013) set out to reexamine the nature of the RAGHMGB1 interaction in the process of recombination to assess the order

protein (TBP) (the HMGB1-TBP-TATA complex) and affected the formation of the pre-initiation complex [60]. However, further work is warranted to confirm this inhibitory role of HMGB1 in the process of transcription. Hence, the effects of HMGB1 on chromatin structure may affect the extent of accessibility of DNA repair machinery to the chromatin and may also affect the transcription of genes related to DNA repair, thereby affecting DNA repair efficiency. 3. Roles of HMGB1 in immunological functions In addition to DNA repair, HMGB1 has important roles in immunerelated functions. It is appreciated that HMGB1 can function as a cytokine and elicit varying immunological responses [20,21,61]; however, its interaction with DNA can also have an impact on the immunological outcomes, which will be discussed in the subsequent sections. 3.1. HMGB1 and V(D)J recombination: Building the immune cell repertoire V(D)J recombination is a process of somatic recombination that results in the production of B cell and T cell antigen receptors. This process has two broad steps: i) cleavage where a DSB is mediated by the RAG1 and RAG2 recombinases, and ii) ligation where non-homologous end joining (NHEJ) repairs the cleaved DNA sequences. V(D)J recombination is initiated by the recognition of conserved DNA sequences referred to as the recombination signal sequences (RSS) flanking the V, D, and J coding sequences, by the RAG recombinases. The structure of the RSS is unique such that each RSS has a conserved heptamer and nonamer element. These are separated by either 12 or 23 nucleotide long spacer sequences with less sequence conservation than the RSS. A characteristic of V(D)J recombination is that this process can only take place between RSS elements with different lengths of the spacer sequence (the 12/23 rule) [62–64]. Upon recognition and cleavage by the recombinases, four broken DNA ends result that can form hairpin structures, which are subsequently repaired by NHEJ to form the coding and signal sequences [62,63,65]. The RAG recombinases not only facilitate the cleavage reaction but also the joining of the coding sequences [66]. Coordinated action of several proteins is required for V (D)J recombination. In this regard, several in vitro studies have found that HMGB1 and/or HMGB2 can impact V(D)J recombination by facilitating the binding and RAG1/2-mediated cleavage at the RSS [67,68]. A substantial body of literature points to the architectural role of HMGB1 (and perhaps HMGB2), where it binds to bent DNA structures and stimulates further bending of DNA to facilitate the desired reaction outcomes in the context of V(D)J recombination. To understand the role of HMGB1 in this process Mo et al. (2000) sought to characterize its function prior to the cleavage reaction. Using EMSAs and UV crosslinking experiments they showed that HMGB1 enhanced the specificity of the RAG proteins for both the 12 and 23 RSS, thereby assisting in formation of a stable complex on the DNA. Interestingly, they demonstrated differences in the localization of HMGB1 in complexes with the RAG proteins at the 12RSS and 23RSS. They showed that in a complex with RAG1/2, HMGB1 localized in the heptamer and adjacent spacer regions in the 12RSS. However, in the 23RSS this complex localized only in the spacer region. This difference in localization was hypothesized to be important for introducing differential bending patterns on both the RSS complexes, which was thought to play a role in distinguishing the 23RSS complex from the 12RSS complex, thereby assisting in enforcing the 12/23 rule [19]. More recently, Ciubotaru et al. (2015) used fluorescence resonance energy transfer (FRET) to analyze the architecture with respect to bending in the RAG-RSS complexes formed during the cleavage reactions. Their results revealed a large bend in the 23RSS complex, which required the presence of HMGB1. Their experimental system identified bends in regions predicted previously by other groups. For example, a 5

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[86]. Since this domain was thought to engage another HMGB1 receptor, receptor for advanced glycation end products (RAGE) [87], a role for RAGE was suspected. Indeed, the CpG ODN increased the binding between HMGB1 and RAGE. Hence, the RAGE receptors engaged with the HMGB1-DNA complex and were then recognized by TLR9 receptors to increase the production of IFNα from B-lymphocytes and pDCs. This observation implicated HMGB1 in autoimmune disorders, which will be discussed in later sections [86]. Similarly, Ivanov et al. (2007) used bone marrow-derived macrophages (BMDMs) and bone marrow-derived DCs (BMDCs) from mice to demonstrate that HMGB1 associated with CpG ODNs and increased the immune potential of these oligonucleotides via a favorable cytokine response. This increase was dependent on the TLR9 receptor. Mechanistically, treatment of cells with the CpG ODNs resulted in an increased production of HMGB1, and HMGB1 was shown to associate with CpG and trigger responses of IL-6, IL-12, and TNFα. The increase in these responses was not due to increased uptake of CpG ODN by the cells but was due to the increased formation of CpG DNA/TLR9 complexes by HMGB1. Using confocal microscopy, they demonstrated that in normal unstimulated cells, HMGB1 pre-associated with TLR9 and when treated with CpG ODN this complex localized to the early endosome to mount the appropriate cytokine response. Additionally, this effect was diminished in the absence of HMGB1 and could be rescued by extracellular HMGB1, indicating the importance of HMGB1 in this process [88]. In support of this observation, Yanai et al. (2009) showed that HMGBs (particularly HMGB1) were involved in promiscuous sensing of nucleic acids. They not only bound to a variety of nucleic acid substrates, but their absence diminished immune responses mediated by these nucleic acids via the endosomal TLR3, TLR7, and TLR9 receptors. The cytosolic response was also affected where HMGB-/- and HMGB2-/cells derived from mice exhibited a reduction in the production of inflammatory cytokines, particularly type I IFN. Similar results were seen with transient depletion of HMGBs using siRNAs in MEFs, RAW264.7 macrophages, and NIH/3T3 fibroblasts. In addition, the downstream pathways that were activated in response to these cytosolic receptors were also affected. Hence the authors speculated that the HMGB proteins are part of a system to perform the preliminary role of sensing these nucleic acids before they are channeled into the specific downstream components of the innate immune system [89]. Interestingly, among the newly identified receptors that engage HMGB1, Chiba et al. (2012) have shown that the innate immune response mediated by the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) upon encountering nucleic acids depends on HMGB1 [90]. TIM3 is a critical regulator of both the adaptive and innate immune responses. As a part of its function, it can induce inflammation by increasing secretion of pro-inflammatory cytokines such as TNF and can work in conjunction with the TLRs. TIM3 was shown to bind HMGB1 and alter the innate immune responses to nucleic acids by affecting recruitment of nucleic acids to the endosome. It did so by binding Box A of HMGB1 and competing with nucleic acid binding sites. It was also shown that in the tumor microenvironment the expression of TIM3 by dendritic cells and its interaction with HMGB1 reduced the efficiency of chemotherapy. Hence, these results indicated the potential use of a combination approach to block TIM3 in addition to chemotherapy [90]; however, as suggested by Tang et al. (2012) the role of TIM3 and HMGB1 needs further evaluation [91]. As opposed to a limited number of receptors involved in the endosomal sensing of DNA, the cytosolic/cytoplasmic sensing of DNA occurs via many different receptors. For example, the cGAS/STING pathway is involved in sensing foreign DNA in the cytoplasm. Doublestranded DNA (dsDNA) is the main activator of cyclic GMP-AMP synthase (cGAS), which occurs without sequence specificity, enabling it to respond to a wide variety of DNA sequences. cGAS is converted into a secondary messenger cyclic GMP-AMP (cGAMP), which binds the stimulator of interferon genes (STING) and activates it to produce type I

of binding of these proteins. Using biotinylated DNA pull-down assays and fluorescence anisotropy experiments they found that HMGB1 bound the RAG-DNA complex with higher affinity than either component alone. They suggested that for recombination to occur HMGB1 might be recruited to a RAG1-DNA complex as opposed to binding of a RAG1-HMGB1 complex to DNA (an RSS element in this context). The binding pattern in that order could also explain the high affinity and observed stability of the HMGB1-RAG-DNA complex as opposed to the traditional transient interactions of HMGB1 with its substrates. Overall, this observation reemphasized the importance of HMGB1 in the various steps of V(D)J recombination [75]. More recently, Thwaites et al. (2019) sought to examine the importance of HMGB1 in V(D)J recombination in cells. They performed a combination of in vitro assays and extrachromosomal recombination assays in NIH3T3 cells with WT RAG1 and mutated versions of RAG1 (found in patients with immunodeficiency). Among the mutants studied, the R401W mutant affected HMGB1 binding and RAG-mediated cleavage in vitro, and substantially reduced recombination in cells. Further analysis revealed that the association of HMGB1 with the RAG-DNA complex was affected by the R401W mutation. Because the mutant protein retained its catalytic activity, the authors suggested that its altered function may be due to the inability of HMGB1 to bind to the mutant RAG-DNA complex [76]. In summary, while HMGB1 may interact with several DNA repair proteins (e.g. Ku, DNA-PK and DNA ligase IV) [31] to facilitate V(D)J recombination, it may also assist in providing a favorable architecture to facilitate optimal activity of the RAG recombinases. 3.2. HMGB1 and foreign nucleic acids: Implications in innate immunity In addition to the receptors that interact with a variety of antigens to mount immune responses, the mammalian immune system consists of a complex repertoire of cells that are involved in stimulating a response to infection as well as tissue damage. One of the many ways this can be achieved is by using DNA and RNA from pathogens or selfmolecules to activate the immune system. One system involved in the detection of foreign nucleic acids is present in the endosomal compartment viz. the toll-like receptors (TLRs); another system is present in the cytoplasm. The characteristic of both systems is the production of type I interferon (IFN) cytokines [77,78]. As mentioned above, TLRs, which are essential in responding to foreign nucleic acids, are an important component of the human innate immune system. The TLR family of receptors have evolved to respond to different types of ligands [79]. Among these, TLR3 and TLR7 function as receptors for doublestranded RNA (dsRNA) and single-stranded (ssRNA)/short dsRNA, respectively, and TLR9 specifically responds to bacterial or self CpG DNA [79]. Bacterial DNA has a high frequency of unmethylated CG dinucleotides relative to vertebrate DNA (˜20-fold greater in bacterial than that in vertebrate DNA) and these motifs are known stimulators of innate immune responses [80]. A similar immunostimulatory effect can also be recapitulated by synthetic cytosine-guanine oligodeoxynucleotides (CpG ODN) which mimic the CpG content of bacterial DNA [81]. The TLR9-mediated response to CpG DNA is restricted to the endosomal compartment, a mechanism which helps the cell to avoid activation of immune responses to “self” DNA [82]. Typically, upon encountering CpG DNA, TLR9 is cleaved, and following subsequent downstream reactions leads to the activation of type I IFN genes. TLR9 receptors show a high expression on plasmacytoid dendritic cells (pDCs) when responding to infections and produce elevated levels of type I IFNs [83]. It is known that HMGB1 can bind to other TLRs, e.g., TLR2 and TLR4 and stimulate immune responses [84,85]. Interestingly, HMGB1 can bind to TLR ligands, such as nucleic acids and augment activation of TLRs, particularly the TLR9. In support of this Tian et al. (2007) observed an increase in IFNα and tumor necrosis factor when pDCs isolated from bone marrow cells were stimulated with HMGB1-CpG complexes as opposed to HMGB1 or CpG alone. On further analysis, it was seen that domain B of HMGB1 led to increased production of IFNα 6

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a role in overcoming tolerance to self DNA in SLE. This resulted in the formation of immune complexes that elicited the production of autoantibodies, which contributed to the pathogenesis of SLE [103]. To provide a mechanistic understanding of SLE, Wen et al. (2013) studied auto-antibody generation and found that not only were antidsDNA antibodies produced in response to circulating DNA-containing immune complexes but HMGB1, as a part of the immune complex, was essential in the production of the anti-dsDNA antibodies. This was achieved via the involvement of the TLR2/MyD88/mir-155 pathway [107]. In addition, Abdulahad et al. (2011) found that apart from elevated levels of HMGB1 in the sera of SLE patients, there was an associated increase in anti-HMGB1 antibodies as measured by enzyme linked immunosorbent assay (ELISA), leading them to hypothesize a role for HMGB1 and anti-HMGB1 immune complexes in the pathogenesis of SLE [108]. Apart from the immune complex deposits in various organs and autoantibodies produced in response to the circulating immune complexes, another feature of SLE disease pathogenesis is an increase in the production of type I interferons. Interestingly, the TLR9 receptor, which was thought to engage only bacterial CpG DNA, was also implicated in recognizing “self” DNA-containing immune complexes in SLE. Tian et al. (2007) showed that HMGB1-DNA immune complexes, via binding to RAGE and subsequently to TLR9, led to an increased production of IFNα from immune cells [86].

interferon [92]. Recently, Andreeva et al. (2017) found that the length of DNA plays a role in the activation of cGAS, and HMGB1 may play a role in cGAS-mediated sensing of long DNA molecules. HMGB1, along with transcription factor A mitochondrial (TFAM), assisted in rearranging DNA in the form of U-turns thereby assisting in cGAS-mediated DNA sensing [93]. 3.3. HMGB1 and self-nucleic acids: Implications in autoimmunity Under normal conditions the pathogen recognition receptors work efficiently to distinguish foreign DNA from “self” DNA; however, the presence of self-antigens can drive the production of autoantibodies, which is a hallmark of various autoimmune disorders [94]. Additionally, when the host immune system malfunctions, it can lead to the recognition of self-DNA as a threat, thereby activating pathways to produce cytokines, particularly the type I IFN, which can manifest into autoinflammatory and autoimmune disorders [83,95]. HMGB1, which can stimulate the production of proinflammatory cytokines and mount a chronic inflammatory response, has been implicated in the pathogenesis of such autoimmune disorders [21,96]. Another feature associated with autoimmune disorders is dysregulation of apoptosis, and a failure to clear apoptotic cells has been linked to the pathogenesis of various autoimmune diseases, reviewed in [97,98]. Fragmented nucleosomes are present in apoptotic cells [99,100] and typically these apoptotic cells are cleared quickly by phagocytosis, thereby preventing the release of these nucleosomes [101]. However, if the apoptotic cells persist or there is a delay in clearance, then nucleosomes from these cells can be released [102]. For example, systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the presence of autoantibodies against nucleosomes and dsDNA. It has also been observed that blood samples of SLE patients contain detectable levels of nucleosomes, which may function as autoantigens [102,103]. In fact, the pathogenesis of SLE is associated with the deposition of immune complexes of these autoantibodies in different organs [103]. It has also been observed that differentiated macrophages from SLE patients display a reduction in and a delayed response to phagocytosis of apoptotic cells [104]. In addition, for a subset of SLE patients, macrophages of the germinal center showed impaired clearance of apoptotic cells [105]. These persistent and uningested apoptotic cells are therefore likely to undergo secondary necrosis, releasing their nucleosomes, which could serve as a source of autoantigen in SLE [106]. Further studies were undertaken to identify the factors that were involved in the conversion of non-immunogenic nucleosomes and dsDNA to autoantigens by overcoming tolerance to self-molecules. In this context, HMGB1 was found to play a potential role; for example, Scaffidi et al. (2002) showed that in cells undergoing apoptosis, the release of HMGB1 from the nucleus was prevented because of its tight association with the hypoacetylated chromatin. They also showed that in HMGB+/+ MEFs, apoptotic cells did not elicit inflammatory responses under the experimental conditions chosen; however, apoptotic cells undergoing secondary necrosis produced strong inflammatory responses. This was characterized by the presence of a significant proportion of HMGB1 being bound to nucleosomes [87]. HMGB1-DNA complexes can be important for the pathogenesis of SLE, as Urbonaviciute et al. (2008) observed that blood from SLE patients contained HMGB1-nucleosome complexes. Under the conditions of their experiments, they observed an induction in the expression of cytokines from macrophages that were stimulated by HMGB1-nucleosome complexes from apoptotic cells. In contrast, nucleosomes from apoptotic cells lacking HMGB1 or nucleosomes from viable cells did not lead to an induction of cytokine release. Interestingly, in a non-autoimmune mouse model, the nucleosomes from apoptotic cells led to an increase in anti-dsDNA antibodies, which were not seen with nucleosomes from viable cells. Hence, it was hypothesized that HMGB1 present in association with the nucleosomes from a subset of apoptotic cells could play

3.4. HMGB1 and chromatin in immune functions The interaction of HMGB1 with chromatin is dynamic, however, it can form highly stable complexes in a context-dependent manner as seen in apoptotic cells where HMGB1 can form a tight complex with the fragmented nucleosomes. In this case, rather than the modification of HMGB1, it is thought that the hypoacetylated condensed chromatin itself serves as a signal for the observed binding of HMGB1 [5,107]. Interestingly, the interaction of HMGB1 and H1 can have a repressive effect in a gene-specific manner in immune-related functions. For example, El Gazzar et al. (2009) reported that in a severe systemic inflammation phenotype, transcriptional silencing of TNFα can be achieved via interaction of HMGB1 and H1. This is accompanied by methylation of histone 3 on lysine 9 (H3K9) and binding of a repressor, RelB, to the promoter of TNFα, the coordinated action of which leads to transcriptional repression [109]. 4. Concluding remarks In summary, DNA repair pathways and innate immune responses are critical for survival. While DNA repair mechanisms function to maintain genomic integrity, the innate immune system assists in the protection of the body against foreign entities. Hence, a thorough understanding of these pathways and the various factors involved is crucial. HMGB1 is a ubiquitous and highly versatile molecule which functions in both DNA repair and immune function-related pathways (outlined schematically in Fig. 5). HMGB1 is dysregulated in several cancers and it is associated with autoimmune disorders making it an attractive target for therapy. However, its cytokine and nucleic acid binding roles depend on its cellular location, redox states, and post translational modifications. Hence, these factors need to be taken into consideration when interpreting the effects of this protein on cellular functions. While we have discussed the effects of HMGB1 here, the other members of the HMGB family viz. HMGB2 and HMGB3 also warrant further investigation. These three proteins share a high level of sequence and structural similarity; however, their functions are non-redundant as mice deficient in these proteins exhibit different phenotypes [110–112]. It will be interesting to study the functions of these proteins in different DNA repair mechanisms, as well as different immunemediated functions. Our laboratory is involved in pursuing this line of 7

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Fig. 5. Overview of cellular responses resulting from interactions of HMGB1 with nucleic acids. Interactions of HMGB1 with nucleic acids/nucleosomes can affect a variety of cellular processes. In the nucleus, the interactions of HMGB1 with DNA can impact architecture and consequently affect transcription, chromatin remodeling, DNA repair pathways (NER, BER, MMR, DSBR), and V(D)J recombination. In the extracellular space, CpG DNA released, for example by bacteria, can bind HMGB1 and subsequently engage the RAGE receptors located on the cell surface. This complex is internalized into the endosomes where it can bind the TLR9 receptor and activate a cascade of reactions resulting in activation of IFNα and functions as a driver of innate immunity. HMGB1 can interact with nucleosomes to form immune complexes released from apoptotic cells in autoimmune diseases (e.g. SLE). In this case as well, the immune complexes can engage RAGE and subsequently bind TLR9 to activate production of IFNα and thereby function in the pathogenesis of autoimmune disorders. HMGB1 can also function as a sensor of cytosolic DNA in conjunction with cGAS and TFAM.

work with respect to DNA damage and repair, and we have recently shown that targeting HMGB3 for depletion sensitizes chemo-resistant ovarian cancer cells to cisplatin treatment [113]. Future studies to determine the roles of the HMGB2 and HMGB3 proteins in DNA repair and immune-mediated mechanisms are warranted to better understand the roles of the HMGB family of proteins in disease etiology via alterations in DNA damage, DNA repair, and immune functions.

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