Elsevier

DNA Repair

Volume 38, February 2016, Pages 94-101
DNA Repair

DNA mismatch repair and the DNA damage response

https://doi.org/10.1016/j.dnarep.2015.11.019Get rights and content

Abstract

This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1], [2]. MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted.

Introduction

In addition to its roles in editing replication errors and other functions (see other reviews in this issue and [3]), the MMR system is also implicated in the repair and cytotoxicity of a subset of DNA lesions caused by SN1 DNA alkylators, 6-thioguanine, fluoropyrimidines, cisplatin, UV light and certain environmental carcinogens that form DNA adducts (reviewed in [4], [5], [6], [7]). Defining the exact role of MMR in cell killing resulting from exposure to these DNA damaging agents is complicated by the sometimes broad spectrum of DNA damage and the convergence of multiple repair pathways such as base excision repair (BER), nucleotide excision repair (NER) and double-strand break (DSB) repair pathways and attendant DNA damage signaling pathways (see, e.g., [8], [9], [10], [11]). The SN1 DNA alkylators, e.g., N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), methylnitrosourea (MNU) and the chemotherapy drug temozolomide, methylate all four DNA bases producing a variety of potentially cytotoxic lesions that are substrates for BER. O6-methylguanine-DNA methyltransferase (MGMT) directly reverses O6meG and plays an important role in protecting against cytotoxic effects of SN1 alkylators and preventing tumor formation in vivo [7]. Not unexpectedly, there are numerous clinical implications, and these are discussed in this issue (minireviews by Begum, Heinen, Sijmons [7b–7d]).

In the case of SN1 DNA alkylators, the DDR requires components of the MMR system; the loss of functional MMR proteins, e.g., hMutSα (MSH2-MSH6) or hMutLα (MLH1-PMS2) gives rise to tolerance in which the persistence of potentially cytotoxic lesions is no longer linked to cell death. Tolerance to the SN1 class of DNA alkylating agents was first observed in Escherichia coli strains defective in MMR that exhibited greatly increased resistance to cell killing and was subsequently demonstrated in MMR-deficient mammalian cell lines some of which are almost two orders of magnitude more resistant to cell killing than comparable MMR-proficient cells (reviewed in [12]). In a similar vein, rare cells that survive exposure to alkylating agents oftentimes have accrued mutations that inactivate MMR [13]. Despite constituting only a small fraction of total alkylated DNA lesions, O6me-G is the key contributor to the mutagenic and cytotoxic effects of SN1 alkylators [14]. Low doses of MNNG induce a G2/M cell cycle arrest in the second cell cycle after exposure that is dependent on MMR proteins (reviewed in [15], [16]). A DDR signaling kinase, ATM and Rad3-related (ATR) is activated and licenses a G2/M cell cycle arrest mediated by downstream targets including the checkpoint kinases CHK1, CHK2, and SMC1 and cell division control 25 (CDC25) phosphatases. Apoptosis ensues directed in most cases by phosphorylation of p53 that also requires functional MutSα and MutLα [17].

Section snippets

The DNA damage response

The cellular responses to DNA damage are collectively termed the DNA damage response. The DDR engages signaling pathways that regulate the recognition of DNA damage, the recruitment of DNA repair factors, the initiation and coordination of DNA repair pathways, transit through the cell cycle and apoptosis [18]. The large number of human diseases and syndromes that arise from defects in components of the DNA damage response reflect the importance of the DDR for health and viability [19].

Three

Upstream events and activation of ATR

Recruitment of ATR and its constitutively interacting partner, ATR interacting protein (ATRIP), to damaged DNA was observed to be dependent on an interaction between ATRIP and replication protein A (RPA) bound to single-stranded DNA (ssDNA) [26]. Subsequent work has supported a model in which processing of DNA damage by various repair systems yields a common intermediate consisting of RPA-ssDNA, that, together with a ssDNA–dsDNA junction, serves to activate ATR [24], [27]. Such structures are

Downstream signaling from ATR

Following activation, ATR acts locally at sites of damage and more globally to phosphorylate a range of substrates that execute downstream functions regulating DNA replication origin firing, stabilizing or restarting replication forks, carrying out DNA repair, activating cell cycle checkpoints and signaling apoptosis [25], [27]. Although detailed understanding is not yet in hand, there is evidence of ATR’s involvement in the regulation of replication origin firing to minimize the collision of

DNA methylation and the DDR

A longstanding explanation for how O6meG triggers an MMR-dependent DDR is grounded in the targeting of MMR excision and resynthesis exclusively to the newly synthesized DNA strand (see the minireview by Kadyrova [76b]). DNA synthesis opposite O6meG by replicative polymerases or possibly utilizing a translesion synthesis (TLS) pathway and error-prone polymerases causes misincorporation and produces non-Watson-Crick base pairs including O6meG:T and O6meG:C. These mispairs are recognized by MutSα

Fluorouracil

Exposure of mammalian cells to fluoropyrimidines such as 5-fluorouracil (FU) or 5-fluoro-2′-deoxyuridine (FdU) also evinces a DDR that is dependent on the MutSα and MutLα MMR proteins [94], [95], [96]. FU is widely used in the treatment of a variety of solid tumors including colorectal tumors, and resistance is a challenge in the clinical setting (reviewed in [97]). Determining the mechanism of cell killing by FU is complicated as its metabolite, 5-fluoro-2′-deoxyuridine monophosphate, inhibits

Oxidative damage and DNA adducts

The primary repair pathway for oxidized DNA damage is BER utilizing specific DNA glycosylases that excise the damaged bases followed by cleavage at the abasic site by AP-endonuclease 1 and gap repair involving polβ (see, for example [107]). However, studies in E. coli, S. cerevisiae, murine embryonic fibroblasts and stem cells and human cancer cell lines support a role for MMR in the repair of oxidative DNA damage, specifically 7,8-dihydro-8-oxo-guanine (8-oxoG) mispairs [15], [108]. MMR can

Context and environment

Both the immediate and more global cellular environment can influence the DDR. Recent work reveals important links between MMR function/regulation and chromatin dynamics and the proteins that regulate chromatin structure (see the minireview by Li, [148b]) [149], [150], [151]. Lin and colleagues have examined the MMR-dependent DDR in human pluripotent stem cells (PSCs) exposed to MNNG and find a surprising result. In contrast to somatic cells exposed to MNNG alkylation damage that undergo a G2/M

Conclusions and future directions

The MMR system plays important roles in a number of cellular processes including the DDR. The challenges as have been noted above center on elucidating molecular mechanisms, exploring the interplay with other repair pathways and defining the effects of cellular and spatiotemporal context, all important for understanding fundamental processes relevant to cancer and therapeutic approaches. In vitro reconstitutions of a DDR that is activated by defined DNA damage and includes relevant repair

Acknowledgments

The authors are supported by the Division of Intramural Research of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH.

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