Replication Stress Response Links RAD52 to Protecting Common Fragile Sites

Rad52 in yeast is a key player in homologous recombination (HR), but mammalian RAD52 is dispensable for HR as shown by the lack of a strong HR phenotype in RAD52-deficient cells and in RAD52 knockout mice. RAD52 function in mammalian cells first emerged with the discovery of its important backup role to BRCA (breast cancer genes) in HR. Recent new evidence further demonstrates that RAD52 possesses multiple activities to cope with replication stress. For example, replication stress-induced DNA repair synthesis in mitosis (MiDAS) and oncogene overexpression-induced DNA replication are dependent on RAD52. RAD52 becomes essential in HR to repair DSBs containing secondary structures, which often arise at collapsed replication forks. RAD52 is also implicated in break-induced replication (BIR) and is found to inhibit excessive fork reversal at stalled replication forks. These various functions of RAD52 to deal with replication stress have been linked to the protection of genome stability at common fragile sites, which are often associated with the DNA breakpoints in cancer. Therefore, RAD52 has important recombination roles under special stress conditions in mammalian cells, and presents as a promising anti-cancer therapy target.

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Pathways for maintenance of telomeres and common fragile sites during DNA replication stress

Open Biology ◽

10.1098/rsob.180018 ◽

2018 ◽

Vol 8 (4) ◽

pp. 180018 ◽

Cited By ~ 26

Author(s):

Özgün Özer ◽

Ian D. Hickson

Keyword(s):

Dna Replication ◽

Molecular Mechanisms ◽

Replication Stress ◽

Fragile Sites ◽

Repair Synthesis ◽

Common Fragile Sites ◽

The Face ◽

Dna Replication Stress ◽

Dna Repair Synthesis ◽

Insight Into

Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.

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Structure-Specific Endonucleases and the Resolution of Chromosome Underreplication

Genes ◽

10.3390/genes10030232 ◽

2019 ◽

Vol 10 (3) ◽

pp. 232 ◽

Cited By ~ 10

Author(s):

Benoît Falquet ◽

Ulrich Rass

Keyword(s):

Sister Chromatid ◽

Replication Fork ◽

Genome Stability ◽

Molecular Mechanisms ◽

Chromosome Breakage ◽

Repair Synthesis ◽

Daughter Cells ◽

Oncogene Activation ◽

Dna Repair Synthesis ◽

Replication Intermediates

Complete genome duplication in every cell cycle is fundamental for genome stability and cell survival. However, chromosome replication is frequently challenged by obstacles that impede DNA replication fork (RF) progression, which subsequently causes replication stress (RS). Cells have evolved pathways of RF protection and restart that mitigate the consequences of RS and promote the completion of DNA synthesis prior to mitotic chromosome segregation. If there is entry into mitosis with underreplicated chromosomes, this results in sister-chromatid entanglements, chromosome breakage and rearrangements and aneuploidy in daughter cells. Here, we focus on the resolution of persistent replication intermediates by the structure-specific endonucleases (SSEs) MUS81, SLX1-SLX4 and GEN1. Their actions and a recently discovered pathway of mitotic DNA repair synthesis have emerged as important facilitators of replication completion and sister chromatid detachment in mitosis. As RS is induced by oncogene activation and is a common feature of cancer cells, any advances in our understanding of the molecular mechanisms related to chromosome underreplication have important biomedical implications.

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Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study

Oncogene ◽

10.1038/sj.onc.1210989 ◽

2007 ◽

Vol 27 (23) ◽

pp. 3256-3264 ◽

Cited By ~ 112

Author(s):

P K Tsantoulis ◽

A Kotsinas ◽

P P Sfikakis ◽

K Evangelou ◽

M Sideridou ◽

...

Keyword(s):

Replication Stress ◽

Fragile Sites ◽

Preneoplastic Lesions ◽

Common Fragile Sites ◽

Genome Wide ◽

A Genome ◽

Genome Wide Study

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Multi-BRCT Domain Protein Brc1 Links Rhp18/Rad18 and γH2A To Maintain Genome Stability during S Phase

Molecular and Cellular Biology ◽

10.1128/mcb.00260-17 ◽

2017 ◽

Vol 37 (22) ◽

Cited By ~ 2

Author(s):

Michael C. Reubens ◽

Sophie Rozenzhak ◽

Paul Russell

Keyword(s):

Genome Stability ◽

Genome Instability ◽

Replication Stress ◽

S Phase ◽

Dna Lesions ◽

Brct Domain ◽

Replication Forks ◽

Content Type ◽

Domain Protein ◽

Chromosome Integrity

ABSTRACT DNA replication involves the inherent risk of genome instability, since replisomes invariably encounter DNA lesions or other structures that stall or collapse replication forks during the S phase. In the fission yeast Schizosaccharomyces pombe, the multi-BRCT domain protein Brc1, which is related to budding yeast Rtt107 and mammalian PTIP, plays an important role in maintaining genome integrity and cell viability when cells experience replication stress. The C-terminal pair of BRCT domains in Brc1 were previously shown to bind phosphohistone H2A (γH2A) formed by Rad3/ATR checkpoint kinase at DNA lesions; however, the putative scaffold interactions involving the N-terminal BRCT domains 1 to 4 of Brc1 have remained obscure. Here, we show that these domains bind Rhp18/Rad18, which is an E3 ubiquitin protein ligase that has crucial functions in postreplication repair. A missense allele in BRCT domain 4 of Brc1 disrupts binding to Rhp18 and causes sensitivity to replication stress. Brc1 binding to Rhp18 and γH2A are required for the Brc1 overexpression suppression of smc6-74, a mutation that impairs the Smc5/6 structural maintenance of chromosomes complex required for chromosome integrity and repair of collapsed replication forks. From these findings, we propose that Brc1 provides scaffolding functions linking γH2A, Rhp18, and Smc5/6 complex at damaged replication forks.

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