DNA replication stress triggers rapid DNA replication fork breakage by Artemis and XPF

PLoS Genet. 2018 Jul 30;14(7):e1007541. doi: 10.1371/journal.pgen.1007541. eCollection 2018 Jul.

Abstract

DNA replication stress (DRS) leads to the accumulation of stalled DNA replication forks leaving a fraction of genomic loci incompletely replicated, a source of chromosomal rearrangements during their partition in mitosis. MUS81 is known to limit the occurrence of chromosomal instability by processing these unresolved loci during mitosis. Here, we unveil that the endonucleases ARTEMIS and XPF-ERCC1 can also induce stalled DNA replication forks cleavage through non-epistatic pathways all along S and G2 phases of the cell cycle. We also showed that both nucleases are recruited to chromatin to promote replication fork restart. Finally, we found that rapid chromosomal breakage controlled by ARTEMIS and XPF is important to prevent mitotic segregation defects. Collectively, these results reveal that Rapid Replication Fork Breakage (RRFB) mediated by ARTEMIS and XPF in response to DRS contributes to DNA replication efficiency and limit chromosomal instability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromosome Segregation / physiology
  • DNA Breaks, Double-Stranded
  • DNA Damage / physiology
  • DNA Repair / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endonucleases / genetics
  • Endonucleases / metabolism*
  • Fibroblasts
  • G2 Phase / genetics*
  • Genomic Instability / physiology
  • Holoenzymes / genetics
  • Holoenzymes / metabolism
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Small Interfering / metabolism
  • S Phase / genetics*

Substances

  • DNA-Binding Proteins
  • Holoenzymes
  • Nuclear Proteins
  • RNA, Small Interfering
  • xeroderma pigmentosum group F protein
  • DCLRE1C protein, human
  • ERCC1 protein, human
  • Endonucleases
  • MUS81 protein, human

Grants and funding

RB’s salary was provided by the Fondation de France, #2014 00051605 (https://www.fondationdefrance.org/fr) ALP’s salary was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (http://www.fapesp.br/). Work in JSH’s laboratory is supported by funding from the Institut National du Cancer (PLBIO 2016) (http://www.e-cancer.fr/), the Agence Nationale de la Recherche (ANR PRC 2016)(http://www.agence-nationale-recherche.fr/), and La Ligue contre le Cancer (Equipe labellisée 2017) (https://www.ligue-cancer.net/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.