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Role of the Mre11 Complex in Preserving Genome Integrity

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Role of the Mre11 Complex in Preserving Genome Integrity G C A T T A C G G C A T genes Review Role of the Mre11 Complex in Preserving Genome Integrity Julyun Oh 1,2 and Lorraine S. Symington 2,* 1 Biological Sciences Program, Columbia University, New York, NY 10027, USA; [email protected] 2 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA * Correspondence: [email protected]; Tel.: +1-212-305-4793 Received: 12 November 2018; Accepted: 27 November 2018; Published: 29 November 2018 Abstract: DNA double-strand breaks (DSBs) are hazardous lesions that threaten genome integrity and cell survival. The DNA damage response (DDR) safeguards the genome by sensing DSBs, halting cell cycle progression and promoting repair through either non-homologous end joining (NHEJ) or homologous recombination (HR). The Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex is central to the DDR through its structural, enzymatic, and signaling roles. The complex tethers DNA ends, activates the Tel1/ATM kinase, resolves protein-bound or hairpin-capped DNA ends, and maintains telomere homeostasis. In addition to its role at DSBs, MRX/N associates with unperturbed replication forks, as well as stalled replication forks, to ensure complete DNA synthesis and to prevent chromosome rearrangements. Here, we summarize the significant progress made in characterizing the MRX/N complex and its various activities in chromosome metabolism. Keywords: Mre11; Rad50; Xrs2/Nbs1; Sae2/Ctp1/CtIP; Tel1/ATM; MRX/N; DSB; DNA damage checkpoint; homologous recombination; DNA repair 1. Introduction Genome integrity is constantly threatened by exogenous and endogenous stresses that can result in various types of DNA damage. Double-strand breaks (DSBs), which can arise spontaneously when a replication fork collapses or can be induced by exposure to genotoxic agents such as ionizing radiation (IR), are one of the most cytotoxic forms of DNA damage. Failure to repair a DSB results in loss of genetic information or even cell death, whereas inaccurate repair can generate chromosome rearrangements, such as translocations, inversions, or copy number variations. Even though accidental DSBs pose a significant threat to genome stability, DSBs are necessary intermediates in a number of programmed recombination events, including V(D)J recombination during lymphocyte development, meiosis, and mating-type switching in budding yeast. In all cases, DSBs need to be properly detected and repaired to preserve genomic integrity. Eukaryotic cells have evolved a sophisticated and highly conserved DNA damage response (DDR) system, which consists of a kinase cascade in response to lesion recognition coordinated with various repair mechanisms, to cope with DSBs. The Mre11-Rad50-Xrs2/Nbs1 complex (MRX in budding yeast, MRN in organisms with Nbs1 replacing Xrs2) orchestrates all stages of the DDR, including sensing the initial lesion, activating checkpoint signaling, driving specific repair pathways, and structurally bridging the participating DNA molecules together. The MRE11, RAD50, and XRS2 genes were originally identified by their requirement for IR resistance and meiotic recombination in Saccharomyces cerevisiae (budding yeast) [1]. Mre11 and Rad50 are conserved in all domains of life whereas Xrs2/Nbs1 is less conserved than Mre11 and Rad50 and has only been identified in eukaryotes [2]. The proteins form a heterohexameric DNA binding complex containing dimers of Genes 2018, 9, 589; doi:10.3390/genes9120589 www.mdpi.com/journal/genes Genes 2018, 9, 589 2 of 25 each subunit [3,4]. Germline hypomorphic mutations of human MRN complex components are associated with Nijmegen breakage syndrome (NBS), NBS-like disorder and ataxia telangiectasia-like disorder (ATLD), which are characterized by cellular radiosensitivity, immune deficiency, and cancer Genes 2018, 9, x FOR PEER REVIEW 2 of 25 proneness [2,5–7]. In mammals, the MRN complex is essential for cell viability, unlike in yeast, in which theidentified null mutations in eukaryotes are viable[2]. The [protei2]. Inns this form review, a heterohexameric we focus DNA on studiesbinding complex performed containing in S. cerevisiae and refer todimers studies of ineach other subunit systems [3,4]. whereGermline appropriate. hypomorphic mutations of human MRN complex components are associated with Nijmegen breakage syndrome (NBS), NBS-like disorder and ataxia 2. Varioustelangiectasia Roles of the-like MRX/N disorder Complex(ATLD), which in DNA are characterized Damage Recognitionby cellular radiosensitivity, and Repair immune deficiency, and cancer proneness [2,5–7]. In mammals, the MRN complex is essential for cell viability, unlike in yeast, in which the null mutations are viable [2]. In this review, we focus on 2.1. Double-Strand Break Detection and Checkpoint Activation studies performed in S. cerevisiae and refer to studies in other systems where appropriate. The cellular response to DSBs is initiated when the MRX/N complex binds to the broken 2. Various Roles of the MRX/N Complex in DNA Damage Recognition and Repair DNA ends within minutes of their generation [8]. MRX/N is normally diffused evenly throughout the nucleus2.1. until Double a-Strand lesion Break induces Detection the and Checkpoint redistribution Activation of the proteins to the damaged site in high concentrationThe [9– cellular11], indicating response to that DSBs the is initiated complex when normally the MRX/N surveys complex thebinds nucleus to the broken for aDNA binding site. MRX/N scansends within along minutes the DNA of their via generation facilitated [8]. MRX/N diffusion is normally to detect diffused free evenly ends [throughout12]. After the binding to DSBs, MRX/Nnucleus recruits until a thelesion transducing induces the kinaseredistribution Tel1/ATM of the andprote activatesins to thethe damaged DNA damagesite in high checkpoint- concentration [9–11], indicating that the complex normally surveys the nucleus for a binding site. signaling cascadeMRX/N scans (Figure along1 )[the2 DNA]. Tel1/ATM via facilitated is adiffusion member to detect of the free PIKK ends family,[12]. After characterized binding to DSBs, as a serine/ threonine proteinMRX/N kinaserecruits withthe antransducing N-terminal kinase HEAT Tel1/ATM repeat domainand activates and C-terminal the DNA kinase damage domain [13]. Mutationscheckpoint in the ATM-signaling gene cascade are (Figure associated 1) [2]. Tel1/ATM with ataxia is a member telangiectasia of the PIKK (A-T), family, characterized a human syndrome characterizedas a serine/threonine by neurodegeneration, protein kinase with sensitivity an N-terminal to IR, HEAT immunodeficiency, repeat domain and C- andterminal predisposition kinase to domain [13]. Mutations in the ATM gene are associated with ataxia telangiectasia (A-T), a human cancer [14syndrome]. The cellular characterized phenotype by neurodegeneration, of A-T is similar sensitivity to NBS to and IR, ATLD immunodeficiency, even though and the clinical manifestationspredisposition of the diseases to cancer differ.[14]. The The cellular N-terminal phenotype HEAT of A- domainT is similar of Tel1/ATMto NBS and ATLD physically even interacts with the conservedthough the clinical Tel1/ATM-interacting manifestations of themotifs diseases at differ. the The C-terminus N-terminal of HEAT Xrs2/Nbs1 domain of [ 15Tel1/ATM–18]. Tel1/ATM kinase activityphysically is stimulated interacts with by the MRX/N conserved binding Tel1/ATM to-interacting protein-bound motifs at DNAthe C-terminus ends but of Xrs2/Nbs1 is independent of [15–18]. Tel1/ATM kinase activity is stimulated by MRX/N binding to protein-bound DNA ends but the Mre11is nuclease independent activity of the [ 19Mre11,20]. nuclease ATP-driven activity conformational [19,20]. ATP-driven changes conformational in the MRX/Nchanges in complex the have been shownMRX/N to regulate complex Tel1/ATMhave been show kinasen to regulate activity Tel1/ATM [21–23], kinase suggesting activity [21 that–23] distinct, suggesting allosteric that effects mediate Tel1/ATMdistinct allosteric activation. effects mediate Human Tel1 ATM/ATM undergoes activation. Human intermolecular ATM undergoes autophosphorylation intermolecular upon interactionautophosphorylation with the MRN complex,upon interaction which with results the MRN in complex, dissociation which ofresults the in inactive dissociation dimer of the into active inactive dimer into active monomers [24]. The exact molecular mechanism of ATM/Tel1 activation monomersremains [24]. The to be exact elucidated. molecular mechanism of ATM/Tel1 activation remains to be elucidated. Figure 1. DamageFigure 1. recognition,Damage recognition, end resection, end resection, and checkpointand checkpoint activation. activation. TheThe Mre11-Rad50-Xrs2Mre11-Rad50-Xrs2 (MRX) (MRX) complex detects double-strand breaks (DSBs) and binds to the break ends (only one end is complex detects double-strand breaks (DSBs) and binds to the break ends (only one end is shown). shown). Xrs2 recruits Tel1 and checkpoint signaling is activated. Resection follows a two-step, Xrs2 recruitsbidirectional Tel1 and mechanism. checkpoint MRX, signaling together with is activated.its cofactor Sae2, Resection initiates followsresection by a two-step,endonucleolytic bidirectional mechanism.cleavage MRX, oftogether the 5′-terminated with its strand, cofactor generating Sae2, an initiates entry site resection for long-range by endonucleolyticresection machineries, cleavage of 0 the 5 -terminated strand, generating an entry site for long-range resection machineries, Exo1
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