YANG Chun-ying

(1. Putuo District people’s Hospital, Shanghai 200060, China; 2. Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, USA)

Chromatin Remodeling and DNA Repair

YANG Chun-ying1,2

(1. Putuo District people’s Hospital, Shanghai 200060, China; 2. Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, USA)

DNA damage can be induced by environmental toxicants and also endogenous sources such as reactive oxygen species or errors during DNA replication and metabolism. If these damage are not repaired, it will cause genome instability thus leading to cancer, aging, immune dysfunction, and neurodegenerative diseases. There are mainly four DNA repair pathways for those DNA damage, including DNA double strand break repair, nucleotide excision repair, base excision repair and mismatch repair. All the repairs must be processed within the context of chromatin. Growing evidence show that nucleosome organization and chromatin structure surrounding the damage sites regulate the DNA repair machinery to access and repair the DNA damage. This article presents most recent highlights of chromatin remodeling in DNA repairs.

DNA damage; DNA repair; genome instability; chromatin remodeling

Introduction

DNA damage accumulates in cells when exposure to environmental toxins, chemicals, ionizing radiation (IR) and ultraviolet (UV) radiation[1-2]. Endogenous reactive oxygen species (ROS) or errors during DNA replication and recombination and metabolism are another source of DNA damage[3]. If those damage are unrepaired or mis-repaired, it will cause genome instability, thus leading to carcinogenesis or age-related diseases. There are four primary well-studied DNA repair pathways, namely, IR and some drugs induced DNA double strand break repair (DSBR), UV radiation induced nucleotide excision repair (NER), ROS induced oxidized base excision repair (BER), and mismatch repair (MMR). As in most biological processes, DNA repair is coordinated via multi-step signaling mechanisms, including nucleosome remodeling, which may be specific to the cell cycle phase and the chromatin state. As the genome is condensed into chromatin, DNA repair must be regulated at the chromatin level. The intrinsic link between chromatin modifications and DNA repair has been well documented in those four repair pathways. Determining how DNA damage DNA is sensed and corrected in chromatin is critical to our understanding of genome stability and its effects on human diseases including cancer.

Chromatin Remodeling

Chromatin consists of nucleosome and chromatin fiber. Nucleosomes are composed of a core histone octamer wrapped by 147 base-pair (bp) of DNA. The octamer is made of a (H3-H4)2tetramer associated with two H2A-H2B dimers. H1, as a linker, directs the path of DNA between the nucleosomes thus making up the chromatin fiber. Chromatin structure and nucleosome packing represent a significant barrier to the efficient detection and repair of all kinds of DNA damage. Accumulating evidences demonstrate that chromatin remodeling has a regulatory function in DNA replication, recombination and repair. The "access-repair-restore" model shows the impact of chromatin on DNA repair[4], which provides a molecular framework for chromatin dynamics in response to DNA damage and repair those damage.

Histone modification is the most well documented mechanism in altering chromatin structure in DNA repair, including phosphorylation, methylation, acetylation, ubiquitination and SUMOylation[5]. Those histone modifications can change chromatin to either open or condense the chromatin structure in a dynamic way. Namely methylation/demethylation, acetylation/deacetylation, ubiquitination/deubiquitination,phosphorylation/dephosphorylation, SUMOylation/deSUMOylation work likely as switchers to open or close chromatin structure for efficient repair. Therefore, large protein complexes are involved in these processes. Elucidating the dynamic interplay of histone post-translational modification and chromatin associated proteins will help understand how DNA damage are repaired in chromatin.

Chromatin Remodeling during DSB Repair

DNA double strand breaks are considered to be the most lethal type of DNA damage. Ionizing radiations, genotoxic chemicals, and therapeutic treatment including chemotherapy and radiation therapy can cause DSBs. Failure in repairing DSB can cause genomic instability thus leading to tumorigenesis, aging and neurogenesis. DSBs are repaired mainly via three different repair pathways, namely the high fidelity homologous recombination (HR), error-prone non homologous end joining (NHEJ), and alternative end joining (Alt-EJ). The chromatin factors mediating repair of these lesions have been extensively investigated. In response to DSBs, the MRN complex (MRE11, NBS1 and Rad51) will recruit the ataxia telangiectasia-mutated (ATM) kinase to the DSBs sites, thus activating ATM kinase by auto-phosphorylation on serine 1981[6]. The activated ATM will phosphorylate H2AX on serine 139 which is called γH2AX[7-8], to amplify the damage signal. Then DSB repair machinery are recruited to DSBs sites for efficient repairing. The γH2AX is the most well-documented histone modification in response to DSBs, and is also considered as a DSB marker monitoring if the DSBs get repaired or not.

In addition to γH2AX, other histone modifications are also required for efficient DSBs repair. H3 K79 methylation and H4 K20 dimethylation (H4K20me2) are recognized by 53BP1 at the DSBs[9-11]. H3 K9 trimethylaiton (H3K9me3) activates TIP60 histone acetyl-transferase (HAT) activity at the damage site[11]. Both Histone H4 and ATM kinase are acetylated by TIP60 and acetylated ATM activates ATM kinase to further stimulate γH2AX formation[12-13]. The H4K16 acetylation mediated by another HAT MOF, recruits repair proteins MDC1, 53BP1 and Brca1 to the DSB sites[14-16]. H2B K120 monoubiquitination is required for recruitment of both HR and NHEJ repair proteins, mightily by regulating chromatin condensation thereby facilitating the repair machinery at DSB sites[17-18]. RNF8 and RNAF168 mediated H2A/H2A.X ubiquitination retains 53BP1 and Brca1 at the break site[19-21]. E3 SUMO ligases PIAS1 and PIAS4 are required for the recruitment of DNA repair proteins to DSBs[22]. SUMOylation is becoming a hot spot in DNA double strand breaks response and repair[23-24]. The SUMOylation sites of histones need to be determined in the future studies.

Chromatin Remodeling during Nucleotide Excision Repair

The environmental mutagen UV light induces 6-4 pyrimidone photoproduts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs) which result in an abnormal DNA structure with lesion. NER removes such bulky DNA adducts that distort the double helix of DNA. There are two major NER subpathways which depend on the lesion in transcribed strand or not. One is transcription-coupled repair (TCR) which repairs the damage on the transcribed strands of transcribing genes and involves RNA polymerase II in damage recognition. The other is global genomic repair (GGR) which repairs damage that occurs on all DNA including nontranscribed and repressed regions of the genome, requiring a unique subset of proteins to recognize the DNA damage. The primary difference between TCR and GGR is the damage recognition step. Once the damage is recognized and theses two pathways use the same repair proteins in the following steps in a "cut-and-paste-like" mechanism[25]. The 10-subunit TFIIH complex and XPG are recruited to the lesion. ERCC1/XPF incise the DNA followed by DNA synthesis and strand ligation steps to complete the repair.

Chromatin structure must be altered during NER pathways because histones H3K9 and H4 K16 were rapidly acetylated after UV radiation, thus recruiting the transcription factor E2F1 which interacts with HAT GCN5[26-28]. H3K56 deacetylation has been promptly triggered by UV irradiation which promotes the recruitment of repair factors including chromatin remodelers to relax the chromatin structure allowing the NER complex to access the damage sites[29-30]. Once the damage gets repaired, two histone chaperones, anti-silencing function 1A (ASF1A) and chromatin assembly factor 1 (CAF-1), facilitate H3K56 acetylation back by recruiting HAT p300[31]. H3K79 methylation is highly increased after UV irradiation only in GGR pathway[32-33]. Histone H2A K119 ubiquitination is induced in response to UV-induced DNA damage and may function as a recognition signal for GGR pathway[34]. Most of the studies about NER and chromatin remodeling are in yeast model. Even functional human homologs can be found and the NER pathways are evolutionally conserved, it would be interesting and helpful to study the histone medications during NER in mammalian cells.

Chromatin Remodeling during Base Excision Repair

ROS can induce oxidized bases, abasic (AP) sites, and single-strand breaks (SSBs). Without repair, DNA lesions would cause mutations resulting in cytotoxicity and cell death and also carcinogenesis. The BER pathway, highly conserved from bacteria to the humans, is responsible for repair of oxidized base lesions and SSBs. Defective BER has been linked to cancers, immune dysfunction, neurodegenerative diseases, and ageing. BER is initiated by a DNA glycosylase (DG) that recognize and excise damaged bases, leaving an abasic site. Then a base gap is left after the apyrimidinic/apurinic endonuclease (APE) cleaving the abasic site. Following the insertion of the missing base by DNA polymerase, DNA ligase seals the nick.

Unlike other three repair pathways, the chromatin remodeling in BER is less studied though the link between chromatin remodeling and BER has been connected. Growing evidence indicate the involvement of chromatin remolding in BER pathway. For example, USP7, a deubiquitinase (DUB) which can remove ubiquitin from histone H2Binvitro[35-36], ensures the repair rate of oxidative bases by enhancing the accessibility of DNA to the chromatin, indicating H2B ubiquitination state regulating BER in an unknown mechanism. Therefore, it′s very interesting area for further study. Another evidence is the thymine DNA glycosylase (TDG) and the HAT p300 form a complex in chromatin which is competent for histone acetylation[37]. More recently, the big subunit of chromatin assembly factor 1, CHAF1A, has been reported that it inhibits the DG activity of NEIL1 by association with NEIL1 only in chromatin fraction[38]. In addition, some research groups performed theinvitrostudies using a nucleosome-containing template and demonstrated that BER enzymes can function properly[32, 39]. However we still don′t know theinvivomechanism. To date, no other histone modifications have been shown in affecting BER. So it would be interesting to determine the chromatin factors and histone modifications involved in BER in the future.

Chromatin Remodeling during Mismatch Repair (MMR)

Base mismatches, erroneous insertion, deletion, and mispairs of bases arise during replication or recombination, which are repaired via MMR. MMR is a highly conserved pathway in all species that plays an important role in maintaining genomic stability. Defects in MMR increase the spontaneous mutations result in tumorigenesis[40-42]. In mammalian cells, MMR is initiated by MutSα (MSH2 and MSH6 heterodimer) recognizing a base-base mismatch or MutSβ (MSH2 and MSH3 heterodimer) recognizing a small insertion-deletion mispair[43-44]. Then MutLα (MLH1-PMS2 heterodimer) possessing an ATPase activity is recruited to the DNA damage site and harbor latent endonuclease activity that excise the nicks[45-47].

MMR also occurs on chromatin. MutSα can disassemble nucleosomes on heteroduplex DNA but it is insufficient to support MMR on chromatin, indicating additional chromatin remodeling factors are required for efficient MMR[48]. CAF-1 has recently been reported to facilitate nick-dependent nucleosome assembly during MMR[47]. CAF-1 interacts with MutSα, PCNA, RPA and other MMR factors. CAF-1 suppresses the MMR activity in response to a DNA methylating agent[49]. Histone modification also regulates MMR. H3K36 trimethylation (H3K36me3) interacts with MSH6 through its Pro-Trp-Trp-Pro (PWWP) domain[50]. H3 acetylation on lysine 115, 122 and 56 has been reported to enhance the remodeling function of MutSα[48]. The nucleosome disassembly activity of MutSα was dramatically increase by histone H3T118 phosphorylationinvitro[51]. Theinvivoinvestigation on H3 phosphorylation needs to be further investigated.

Conclusion

In this paper, the histone modification and chromatin structure in all DNA repair pathways have been extensively described. Despite the accumulating evidence indicates the regulatory roles of chromatin remodeling in DNA repairs, how histone modification alter chromatin structure and how chromatin remodelers integrate with these pathways are still unclear. Additionally, despite the emerging picture showing the involvement of chromatin structure in regulation of MMR and BER, more histone modifications remain to be identified. Collectively, elucidating the mechanism of chromatin remodeling in DNA repair would provide new insights into the mechanisms of tumorigenesis and the new molecular targets for cancer treatment.

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2017-04-06；

2016-04-28

楊春英，博士，副研究員，研究方向為表觀遺傳與DNA損傷修復(fù)調(diào)控重大疾病和癌癥的發(fā)生發(fā)展，E-mail: yangchy930@gmail.com

染色質(zhì)重構(gòu)與DNA損傷修復(fù)

楊春英1,2

(1. 上海市普陀區(qū)人民醫(yī)院， 上海 200060; 2. 美國康奈爾大學(xué)衛(wèi)理醫(yī)院 放射腫瘤學(xué)系， 休斯頓 77030)

外界環(huán)境毒素和細(xì)胞內(nèi)源DNA復(fù)制和代謝過程中的錯誤及活性氧都會造成DNA的損傷。如果這些DNA損傷得不到修復(fù)，會造成基因組不穩(wěn)定，進而導(dǎo)致癌癥、衰老、免疫系統(tǒng)失調(diào)和神經(jīng)退行性疾病。目前研究最為詳細(xì)的有4種DNA修復(fù)途徑，即DNA雙鏈斷裂修復(fù)、核苷酸切除修復(fù)、堿基切除修復(fù)和錯誤配對修復(fù)。所有的DNA修復(fù)都發(fā)生在染色質(zhì)上。越來越多的證據(jù)表明核小體組織和染色質(zhì)結(jié)構(gòu)調(diào)控DNA修復(fù)蛋白復(fù)合物進入DNA損傷處并進行有效的修復(fù)。就染色質(zhì)重構(gòu)在DNA損傷修復(fù)中的調(diào)控機制的最新研究進行綜述。

DNA損傷；DNA修復(fù)；基因組不穩(wěn)定；染色質(zhì)重構(gòu)

Q523

A

2095-1736(2017)03-0069-05

doi∶10.3969/j.issn.2095-1736.2017.03.069