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RNF8-independent Lys63 poly-ubiquitylation prevents genomic instability in response to replication-associated DNA

Chantal H M A Ramaekers1, Twan van den Beucken1, Robert G Bristow2

  • 1Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada ; Maastricht Radiation Oncology (MaastRO) Lab, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Plos One
|March 4, 2014
PubMed

Insights

A novel DNA repair pathway involving K63-ubiquitylation is crucial for maintaining genome stability during replication stress. This pathway, independent of RNF8, prevents mutations and chromosomal damage from replication-associated DNA double-strand breaks (DSBs).

Area of Science:

  • Molecular Biology
  • Genetics
  • Cellular Biology

Background:

  • DNA double-strand breaks (DSBs) trigger cellular repair mechanisms involving protein modifications like ubiquitylation.
  • K63-linked polyubiquitin chains, formed by RNF8 and RNF168, are known to mediate the recruitment of repair proteins to ionizing radiation (IR)-induced DSBs.

Purpose of the Study:

  • To investigate the role of K63-ubiquitylation in the cellular response to replication-associated DSBs.
  • To determine if K63-ubiquitylation contributes to cell survival and genome stability during replication stress.

Main Methods:

  • Utilized knockdown and knockout cell lines to suppress K63-ubiquitylation.
  • Assessed mutation frequency, chromosomal aberrations, and 53BP1 foci formation in response to replication-associated DSBs.
  • Investigated the involvement of RNF8 in this repair pathway.

Main Results:

  • Suppression of K63-ubiquitylation significantly increased large-scale mutations and chromosomal aberrations in response to replication-associated DSBs.
  • A defect in S-phase DNA repair was observed, indicated by increased residual 53BP1 foci.
  • The requirement for K63-ubiquitylation in repairing replication-associated DSBs was found to be RNF8-independent, contrasting with IR-induced DSBs.

Conclusions:

  • A novel K63-ubiquitylation-dependent DNA repair pathway exists for replication-associated DSBs.
  • This pathway is essential for maintaining genome integrity and cell survival under replication stress.
  • The pathway's RNF8-independence highlights distinct mechanisms for different types of DNA damage.

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