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H3k36me3, Message from Chromatin to DNA Damage Repair Zhongxing Sun†, Yanjun Zhang†, Junqi Jia, Yuan Fang, Yin Tang, Hongfei Wu and Dong Fang*

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H3k36me3, Message from Chromatin to DNA Damage Repair Zhongxing Sun†, Yanjun Zhang†, Junqi Jia, Yuan Fang, Yin Tang, Hongfei Wu and Dong Fang* Sun et al. Cell Biosci (2020) 10:9 https://doi.org/10.1186/s13578-020-0374-z Cell & Bioscience REVIEW Open Access H3K36me3, message from chromatin to DNA damage repair Zhongxing Sun†, Yanjun Zhang†, Junqi Jia, Yuan Fang, Yin Tang, Hongfei Wu and Dong Fang* Abstract Histone marks control many cellular processes including DNA damage repair. This review will focus primarily on the active histone mark H3K36me3 in the regulation of DNA damage repair and the maintenance of genomic stability after DNA damage. There are diverse clues showing H3K36me3 participates in DNA damage response by directly recruiting DNA repair machinery to set the chromatin at a “ready” status, leading to a quick response upon damage. Reduced H3K36me3 is associated with low DNA repair efciency. This review will also place a main emphasis on the H3K36me3-mediated DNA damage repair in the tumorigenesis of the newly found oncohistone mutant tumors. Gain- ing an understanding of diferent aspects of H3K36me3 in DNA damage repair, especially in cancers, would share the knowledge of chromatin and DNA repair to serve to the drug discovery and patient care. Keywords: H3K36me3, DNA damage, Oncohistones, Homologous recombination, Nonhomologous end-joining, DNA mismatch repair, Clear cell renal cell carcinoma, Acute myeloid leukemia, Difuse intrinsic pontine glioma Background Histone methylations usually occur on the argi- In eukaryotes, the genomic DNA is packaged into chro- nine or lysine residues. Histone H3 is methylated at matin to maintain the higher order structure. Nucleo- lysine 36 (H3K36) with mono-, di- and tri-methylations some, the smallest subunit of chromatin, consists of (H3K36me1/me2/me3). In yeast, Set2 is the solo enzyme 146–147 base pairs of DNAs wrapped around an octamer responsible for all of these three forms of methylations of core histone proteins, including one H2A–H2B [7]. In mammalian cells, several redundant enzymes, tetramer and two H3–H4 dimers [1]. Te N- and C-ter- including NSD1 [8], NSD2 [9], NSD3 [9, 10], ASH1L [11], minal tails of core histones are enriched with basic amino SETD3 [12], SETMAR [13], and SMYD2 [14], are able acids and may undergo post-translational modifcations to mono- and di-methylate H3K36. SETD2, the paralo- during distinct cellular processes, such as gene transcrip- gous protein of Set2, is the only enzyme found to catalyze tion, cell cycle checkpoint, centromere assembly, hetero- the formation of H3K36me3, while there are still argu- chromatin formation, DNA replication and DNA repair ments that it also methylates H3K36 to H3K36me1 and [2–5]. Diferent modifcations have been reported, at H3K36me2 in vivo [15]. Several lines of evidences have least by Mass Spectrometry analysis, on core histones, shown that H3K36me3 plays a role in the transcriptional of which the mostly studied modifcations are meth- activation. H3K36me3 is tightly correlated with actively ylation, acetylation, phosphorylation, ubiquitylation and transcribed genome regions [16, 17]. SETD2, the meth- SUMOylation [6]. yltransferase for H3K36me3, is recruited through the Ser2 phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII) during gene transcription elon- *Correspondence: [email protected] gation, while the Ser5 phosphorylation of RNAPII is the †Zhongxing Sun and Yanjun Zhang contributed equally to this work characteristic of the paused polymerases at promoters Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, [18]. Genome-wide studies show that H3K36me3 dis- China tributes in the gene body in a 3′ end enriched manner © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sun et al. Cell Biosci (2020) 10:9 Page 2 of 9 like the Ser2 phosphorylated RNAPII [19, 20]. In addi- pathway, helicases and nucleases are recruited to resect tion, H3K36me3 acts as a safeguard to prevent aberrant 5′ DNA ends to generate two 3′ single-stranded DNA transcriptional initiation from cryptic gene promoters overhangs. Te 5′ end resection is done by removing a [21, 22]. In yeast, Set2 secures H3K36me3 co-transcrip- short oligonucleotide through the activities of C-termi- tionally and recruits the reduced potassium dependency nal binding protein interacting protein (CtIP) and the 3 small (Rpd3S) through its chromodomain-containing Mre11-Rad50-Nbs1 (MRN) complex, followed by Exo1 subunit ESA1 associated factor 3 (Eaf3), which will then or DNA2-BLM [34]. Phosphorylated replication pro- subsequently deacetylate histones around the transcribed tein A (RPA) binds to the 3′ single-stranded DNA over- gene body regions [23]. Trough this process, cells main- hangs and removes DNA secondary structures which, in tain the deacetylated chromatin to inhibit the cryptic turn, leads to the RAD51 nucleoflament formation. Te transcription. In mammalian cells, SETD2 is recruited RAD51 flament will then promote strand invasion of a to the RNAPII elongation complex through an Spt6:Iws homologous DNA and subsequently the accurate repair axis [24]. However, depletion of SETD2 does not afect of DSBs [34, 35]. Cells can also repair DSBs through the histone acetylation across the gene coding regions, NHEJ. During classical NHEJ, the broken DNA ends are indicating that the H3K36me3 preserves the repressive rapidly bound and blocked by Ku70–Ku80 heterodimer chromatin status independent of histone acetylation. (Ku) which protects the DNA from 5′ end resection and Another important role of H3K36me3 in gene expression holds the broken DNAs in a close proximity [36]. DSBs is to regulate RNA splicing [25]. To regulate the RNA are then processed and joined by the Ligase 4 (Lig4), splicing machinery, H3K36me3 forms an adapter system XRCC4, XLF complex [36]. DSBs can also be repaired with MORF-related gene 15 (MRG15) to recruit splicing by alternative NHEJ pathways, such as microhomology- regulator polypyrimidine tract–binding protein (PTB) mediated end-joining (MMEJ), without the recruitment [26]. Deletion of 3′ splice site of genes causes a shift of of Ku or Lig4. MMEJ is initiated through end resection H3K36me3 from 5′ ends to 3′ ends, despite the fact like HR, but followed by the end-joining through short that mutations of poly(A) site have no apparent efects direct repeats of microhomology [37]. In contrast to HR, on H3K36me3. Moreover, a global inhibition of splic- which recruits homologous sequences outside the DNA ing also triggers the repositioning of H3K36me3 [27]. replication process to promote an error-free DNA repair, Tese results suggest that H3K36me3 and co-transcrip- NHEJ directs ligations of the DSB ends in an error-prone tional splicing complex interact with each other. Since manner throughout the cell cycle. Both repair pathways H3K36me3 is tightly associated with gene expression and depend on the DNA damage sensors, transducers, and RNA splicing, how does H3K36me3 participate in other efectors to detect and repair the breaks. Since all these cellular processes like DNA damage repair? evens happen on the chromatin, the diversity of his- tone modifcations on chromatin may afect the choice Main text between HR and NHEJ. Maintain genome integrity after DNA damage Cells are constantly facing DNA damaging agents from H3K36me3 in the error‑free repair (HR) both endogenous and exogenous origins [28]. Tese Te early clues of the participation of H3K36me3 in DNA bulky DNA lesions need to be repaired by naturally repair are from small scale genetic screening. In Sac- adapted DNA repair machineries [29]. If unrepaired charomyces cerevisiae, overexpression of RPH1 which or misrepaired, DNA lesions may cause the accumula- demethylates H3K36me3 primarily leads to a growth tion of DNA errors and great threat to genome stability, defect in response to UV irradiation [38]. In addition, which is a hallmark of cancer, aging, neurodegenera- the H3K36me3 catalyzing enzyme, Set2, is involved in tion, and immune defciencies [30]. DNA double strand hydroxyurea (HU)-induced replication checkpoint acti- breaks (DSBs) usually arise by the attack of electrophilic vation [39]. Besides these signs of H3K36me3 in DNA molecules like reactive oxygen species, leading to lesions repair, emerging evidences show that Pro-Trp-Trp-Pro in both DNA strands of the double helix [31]. DSBs (PWWP)-domain containing proteins recognize H3 lysine are majorly perceived by ataxia telangiectasia mutated methylation and act as anchors between histone meth- (ATM) kinase which is critical for the immediate DNA ylation and downstream efectors, including 53BP1 [40, damage response (DDR) [32]. ATM phosphorylates and 41]. Te early molecular mechanisms of how H3K36me3 regulates the activity of several substrates in DNA repair, participates in the DSBs were reported in 2012. Psip1 including p53-binding protein 1 (53BP1). To maintain encodes two protein isoforms by alternative splicing, p52 genome stability, cells choose from two diferent path- and p75 [42]. Te p75 isoform, also known as lens epithe- ways to repair DSBs: homologous recombination (HR) lium derived growth factor (LEDGF), is a chromatin-asso- and nonhomologous end-joining (NHEJ) [33]. In the HR ciated protein involved in cancer, auto immune diseases, Sun et al.
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