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DNA Mismatch Repair in the Context of Chromatin Yaping Huang* and Guo‑Min Li

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DNA Mismatch Repair in the Context of Chromatin Yaping Huang* and Guo‑Min Li Huang and Li Cell Biosci (2020) 10:10 https://doi.org/10.1186/s13578-020-0379-7 Cell & Bioscience REVIEW Open Access DNA mismatch repair in the context of chromatin Yaping Huang* and Guo‑Min Li Abstract DNA mismatch repair (MMR) maintains replication fdelity by correcting mispaired nucleotides incorporated by DNA polymerases. Defects in MMR lead to cancers characterized by microsatellite instability. Recently, chromatin mecha‑ nisms that regulate MMR have been discovered, which sheds new light on MMR defciency and its role in tumorigen‑ esis. This review summarizes these chromatin‑level mechanisms that regulate MMR and their implications for tumor development. Background proteins and their modifcations. Indeed, recent studies DNA mismatch repair (MMR) maintains replication have indicated that trimethylation of histone H3 lysine 36 fdelity in a replication-coupled manner, primarily by cor- (H3K36me3) plays a role in MMR by recruiting MutSα to recting misincorporated nucleotides in the nascent DNA replicating chromatin [5]. In addition, chromatin assem- strand [1–4]. Te typical MMR reaction in human cells bly/remodeling factors also interact with MMR proteins comprises three major steps. First, the mismatch rec- to coordinate MMR and nucleosome formation [6, 7]. ognition protein MutSα (MSH2–MSH6 heterodimer) Loss-of-function mutations or promoter hyper-methyl- or MutSβ (MSH2–MSH3 heterodimer) recognizes the ation of MMR genes, such as MSH2 and MLH1, increase mismatch, which triggers concerted interactions with susceptibility to cancers, including hereditary non-poly- proliferating cell nuclear antigen (PCNA) and MutLα posis colorectal cancer (HNPCC), also called lynch syn- (MLH1–PMS2 heterodimer), leading to the recruitment drome [1, 2, 4, 8, 9]. Te demonstration of H3K36me3 as of exonuclease 1 (EXO1) to a single-strand DNA break. an essential component for MMR in vivo [5] may provide Ten, Exo1-catalyzed DNA excises the mispaired base new insights into MMR defciency and cancer suscep- from the nick up to and beyond the mismatch in a man- tibility in the chromatin context. H3K36me3 is a well- ner dependent on MutSα (or MutSβ), MutLα, and repli- known histone post-translational modifcation mark, and cation protein A (RPA). Finally, the DNA gap is flled by its cellular level is regulated by its trimethyltransferase DNA polymerase δ in the presence of PCNA, RPA, and SETD2 and lysine demethylase KDM4 [10]. Inappropri- replication factor C (RFC), followed by DNA ligase I-cat- ate expression of and/or defects in these histone writer alyzed nick ligation. and eraser genes probably infuence cellular H3K36me3 In eukaryotes, DNA is wrapped around histone octam- levels, leading to the loss of MMR function. ers, which, together with DNA, compose nucleosomes Recent studies have also shown that mutations in his- to form chromatin. Tus, all DNA metabolic reactions, tone 3 (H3), particularly H3K36M/I and H3G34V/R, including MMR, are precisely regulated by the struc- which frequently occur in various tumors [11–14], afect tures of chromatin, particularly its component histone H3K36me3 expression levels [15, 16]. Tis review will focus on the most recent developments in the feld con- *Correspondence: [email protected] cerning the regulation of MMR in the context of chroma- Department of Radiation Oncology, University of Texas Southwestern tin and its association with cancer susceptibility. Readers Medical Center, Dallas, TX 75390, USA © 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://crea‑ tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo‑ main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Huang and Li Cell Biosci (2020) 10:10 Page 2 of 8 are also referred to several recent reviews in this area PWWP domain. Tus, yeast MutSα must be recruited [17–20]. by a histone mark diferent from H3K36me3, which is consistent with the report that set2 defciency doesn’t Main text infuence mutation frequency in yeast [25]. A recent H3K36me3 distribution dictates local mutation frequency study revealed that the PWWP domain of MSH6 in Cap- Te biochemistry of MMR is essentially well established, sella rubella interacts better with H3K4me3 than with but how the MMR system is regulated in the chromatin H3K36me3 [26], suggesting that H3K4me3, rather than context is not fully understood. In 2013, Li et al. [5] iden- H3K36me3, is the preferred histone mark for loading tifed H3K36me3 as an important MMR regulator in vivo MutSα to chromatin in plants. Te diference in MutSα by recruiting mismatch recognition protein MutSα to recruitment among diferent organisms may suggest an replicating chromatin through its physical interaction adapted evolution for MMR regulation in the chromatin with the PWWP domain of human MutSα. A recent context, although the canonical MMR function is highly chromatin immunoprecipitation followed by sequencing conserved. Terefore, additional studies are needed to (ChIP-Seq) study [21] has illustrated the genome-wide determine why diferent systems use diferent mecha- distribution of H3K36me3 and MutSα in HeLa cells. Both nisms for MutSα recruitment. H3K36me3 and MutSα are unevenly distributed in chro- matin [10, 21]. H3K36me3 and MutSα are more enriched Chromatin remodeling in MMR in euchromatin, exons, and 3′ gene bodies than in het- MMR occurs in the chromatin context, where nucleo- erochromatin, introns, and 5′ gene bodies, respectively. some obstacles must be handled for efcient repair Consistent with MMR’s genome maintenance role, the before the newly synthesized mismatch-containing H3K36me3–MutSα distribution is inversely correlated DNA is packaged into nucleosomes. Tus, MMR needs with mutation frequencies in these genomic regions, as to coordinate with chromatin remodeling factors and/or the mutation frequencies in euchromatin, exons, and 3′ nucleosome assembly factors to repair misincorporated gene bodies are much lower than in heterochromatin, nucleotides (Fig. 1). CAF-1 is the most studied nucleo- introns, and 5′ gene bodies, respectively. In other words, some assembly factor involved in MMR during replica- the abundance of H3K36me3 and MutSα is inversely cor- tion. CAF-1 directly interacts with MMR components related to the local mutation frequency [21]. MutSα and PCNA, and MutSα inhibits CAF-1-mediated It is known that replication timing determines mutation chromatin assembly [27]. Recent biochemical studies frequency: early replicating genes exhibit lower mutation further indicate that MutSα inhibits CAF-1- and ASF1A- frequencies than late replicating genes. Tis phenomenon H3-H4-dependent packaging of DNA mismatches into can be well explained by the distribution and enrichment (H3–H4)2 tetramers [28]. Tese studies support the idea of H3K36me3/MutSα in chromatin. Analyzing the rela- that MMR occurs before the mismatch is packaged into tionship between replication timing, H3K36me3/MutSα nucleosomes. In addition, CAF-1- and ASF1A-H3-H4- enrichment, and mutation frequency revealed that early dependent nucleosome assembly quickly represses the replicating chromatin regions are highly enriched for unnecessary degradation of the discontinuous strand [7, H3K36me3/MutSα and display a lower mutation fre- 28]. Tus, nucleosome assembly is compatible with MMR quency than late replicating regions, which contain fewer during replication. In contrast to CAF-1, the chromatin H3K36me3/MutSα signals [21]. Tese observations sug- remodeler Smarcad1 is recruited by MSH2 to mismatch- gest that H3K36me3-mediated MMR ensures the replica- containing DNA to exclude nucleosomes from the repair tion accuracy of early replicating genes/chromatin, where site [29]. It is interesting to note that, although MSH2, actively transcribed genes are located. In addition to safe- a subunit of MutSα, can be recruited to chromatin via guarding actively transcribed genes during DNA replica- H3K36me3 [5], a recent study showed that ARID1A, tion, H3K36me3-mediated MMR also appears to protect a subunit of the chromatin remodeling complex SWI/ these genes during transcription by directly or indirectly SNF, recruits MSH2 to the chromatin during replica- removing DNA lesions associated with transcription tion through direct interaction [30]. Histone variants [21]. However, how H3K36me3 regulates MMR in difer- also play important roles in DNA transactions, in addi- ent DNA transactions, e.g., replication and transcription, tion to nucleosome assembly and chromatin remodeling. remains to be investigated. It was reported that deposition of H2A.Z by chromatin It is worth noting that not all eukaryotic cells use remodeling enzyme SWR-C stimulates Exo1 activity and H3K36me3
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