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The MMS22L-TONSL Complex Mediates Recovery from Replication Stress and Homologous Recombination

Research output: Contribution to journalArticle

  • Lara O'Donnell
  • Stephanie Panier
  • Johnny M. Tkach
  • Abdallah Al-Hakim
  • Marie-Claude Landry
  • Cristina Escribano-Diaz
  • Rachel K. Szilard
  • Jordan T. F. Young
  • Meagan Munro
  • Marella D. Canny
  • Nadine K. Kolas
  • Wei Zhang
  • Shane M. Harding
  • Jarkko Ylanko
  • Megan Mendez
  • Michael Mullin
  • Thomas Sun
  • Bianca Habermann
  • Alessandro Datti
  • Robert G. Bristow
  • Anne-Claude Gingras
  • Grant W. Brown
  • Daniel Durocher

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Original languageEnglish
Pages (from-to)619-631
Number of pages13
JournalMolecular Cell
Volume40
Issue number4
DOIs
Publication statusPublished - 24 Nov 2010

Abstract

Genome integrity is jeopardized each time DNA replication forks stall or collapse. Here we report the identification of a complex composed of MMS22L (C6ORF167) and TONSL (NFKBIL2) that participates in the recovery from replication stress. MMS22L and TONSL are homologous to yeast Mms22 and plant Tonsoku/Brushy1, respectively. MMS22L-TONSL accumulates at regions of ssDNA associated with distressed replication forks or at processed DNA breaks, and its depletion results in high levels of endogenous DNA double-strand breaks caused by an inability to complete DNA synthesis after replication fork collapse. Moreover, cells depleted of MMS22L are highly sensitive to camptothecin, a topoisornerase I poison that impairs DNA replication progression. Finally, MMS22L and TONSL are necessary for the efficient formation of RAD51 foci after DNA damage, and their depletion impairs homologous recombination. These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks.

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