DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage

Ryan Mayle; Ian M Campbell; Christine R Beck; Yang Yu; Marenda Wilson; Chad A Shaw; Lotte Bjergbaek; James R Lupski; Grzegorz Ira

doi:10.1126/science.aaa8391

DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage

Ryan Mayle, Ian M Campbell, Christine R Beck, Yang Yu, Marenda Wilson, Chad A Shaw, Lotte Bjergbaek, James R Lupski, Grzegorz Ira

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

153 Citations (Scopus)

Abstract

Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Polδ, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.

Original language	English
Journal	Science
Volume	349
Issue	6249
Pages (from-to)	742-747
Number of pages	6
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.aaa8391
Publication status	Published - 14 Aug 2015

Keywords

Alu Elements
Base Sequence
DNA Breaks, Double-Stranded
DNA Repair
DNA Replication
DNA-Binding Proteins
DNA-Directed DNA Polymerase
Endonucleases
Genomic Instability
Humans
Molecular Sequence Data
Neoplasms
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins

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@article{09532f3831bd41639419c9c68f0e0af0,

title = "DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage",

abstract = "Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Polδ, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.",

keywords = "Alu Elements, Base Sequence, DNA Breaks, Double-Stranded, DNA Repair, DNA Replication, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Endonucleases, Genomic Instability, Humans, Molecular Sequence Data, Neoplasms, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins",

author = "Ryan Mayle and Campbell, {Ian M} and Beck, {Christine R} and Yang Yu and Marenda Wilson and Shaw, {Chad A} and Lotte Bjergbaek and Lupski, {James R} and Grzegorz Ira",

note = "Copyright {\textcopyright} 2015, American Association for the Advancement of Science.",

year = "2015",

month = aug,

day = "14",

doi = "10.1126/science.aaa8391",

language = "English",

volume = "349",

pages = "742--747",

journal = "Science",

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TY - JOUR

T1 - DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage

AU - Mayle, Ryan

AU - Campbell, Ian M

AU - Beck, Christine R

AU - Yu, Yang

AU - Wilson, Marenda

AU - Shaw, Chad A

AU - Bjergbaek, Lotte

AU - Lupski, James R

AU - Ira, Grzegorz

PY - 2015/8/14

Y1 - 2015/8/14

N2 - Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Polδ, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.

AB - Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Polδ, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.

KW - Alu Elements

KW - Base Sequence

KW - DNA Breaks, Double-Stranded

KW - DNA Repair

KW - DNA Replication

KW - DNA-Binding Proteins

KW - DNA-Directed DNA Polymerase

KW - Endonucleases

KW - Genomic Instability

KW - Humans

KW - Molecular Sequence Data

KW - Neoplasms

KW - Saccharomyces cerevisiae

KW - Saccharomyces cerevisiae Proteins

U2 - 10.1126/science.aaa8391

DO - 10.1126/science.aaa8391

M3 - Journal article

C2 - 26273056

SN - 0036-8075

VL - 349

SP - 742

EP - 747

JO - Science

JF - Science

IS - 6249

ER -

DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage

Abstract

Keywords

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