EXO1 suppresses double-strand break induced homologous recombination between diverged sequences in mammalian cells

Chun Chin Chen, Elena Avdievich, Yongwei Zhang, Yu Zhang, Kaichun Wei, Kye-Ryoung Lee, Winfried Edelmann, Maria Jasin, Jeannine R. LaRocque

Research output: Contribution to journalArticle

Abstract

DNA double-strand breaks (DSBs) can be repaired through several mechanisms, including homologous recombination (HR). While HR between identical sequences is robust in mammalian cells, HR between diverged sequences is suppressed by DNA mismatch-repair (MMR) components such as MSH2. Exonuclease I (EXO1) interacts with the MMR machinery and has been proposed to act downstream of the mismatch recognition proteins in mismatch correction. EXO1 has also been shown to participate in extensive DSB end resection, an initial step in the HR pathway. To assess the contribution of EXO1 to HR in mammalian cells, DSB-inducible reporters were introduced into Exo1−/− mouse embryonic stem cells, including a novel GFP reporter containing several silent polymorphisms to monitor HR between diverged sequences. Compared to HR between identical sequences which was not clearly affected, HR between diverged sequences was substantially increased in Exo1−/− cells although to a lesser extent than seen in Msh2−/− cells. Thus, like canonical MMR proteins, EXO1 can restrain aberrant HR events between diverged sequence elements in the genome.

Original languageEnglish (US)
Pages (from-to)98-106
Number of pages9
JournalDNA Repair
Volume57
DOIs
StatePublished - Sep 1 2017

Fingerprint

Homologous Recombination
Repair
Cells
DNA Mismatch Repair
DNA
Stem cells
Polymorphism
Machinery
Proteins
Genes
Double-Stranded DNA Breaks
Genome

Keywords

  • Diverged sequences
  • DNA mismatch repair
  • EXO1
  • Homologous recombination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

EXO1 suppresses double-strand break induced homologous recombination between diverged sequences in mammalian cells. / Chen, Chun Chin; Avdievich, Elena; Zhang, Yongwei; Zhang, Yu; Wei, Kaichun; Lee, Kye-Ryoung; Edelmann, Winfried; Jasin, Maria; LaRocque, Jeannine R.

In: DNA Repair, Vol. 57, 01.09.2017, p. 98-106.

Research output: Contribution to journalArticle

Chen, Chun Chin ; Avdievich, Elena ; Zhang, Yongwei ; Zhang, Yu ; Wei, Kaichun ; Lee, Kye-Ryoung ; Edelmann, Winfried ; Jasin, Maria ; LaRocque, Jeannine R. / EXO1 suppresses double-strand break induced homologous recombination between diverged sequences in mammalian cells. In: DNA Repair. 2017 ; Vol. 57. pp. 98-106.
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AB - DNA double-strand breaks (DSBs) can be repaired through several mechanisms, including homologous recombination (HR). While HR between identical sequences is robust in mammalian cells, HR between diverged sequences is suppressed by DNA mismatch-repair (MMR) components such as MSH2. Exonuclease I (EXO1) interacts with the MMR machinery and has been proposed to act downstream of the mismatch recognition proteins in mismatch correction. EXO1 has also been shown to participate in extensive DSB end resection, an initial step in the HR pathway. To assess the contribution of EXO1 to HR in mammalian cells, DSB-inducible reporters were introduced into Exo1−/− mouse embryonic stem cells, including a novel GFP reporter containing several silent polymorphisms to monitor HR between diverged sequences. Compared to HR between identical sequences which was not clearly affected, HR between diverged sequences was substantially increased in Exo1−/− cells although to a lesser extent than seen in Msh2−/− cells. Thus, like canonical MMR proteins, EXO1 can restrain aberrant HR events between diverged sequence elements in the genome.

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