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Scientific article
Open access
English

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

Published inMolecular cell, vol. 64, no. 6, p. 1127-1134
Publication date2016-12
Abstract

Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.

eng
Keywords
  • DNA recombination
  • DNA replication stress
  • RAD52
  • Break-induced replication
  • Cancer
Funding
  • Swiss National Science Foundation - DNA Damage Checkpoint Pathways [160322]
  • Novo Nordisk Fonden - [NNF 14CC0001]
  • Novo Nordisk Foundation Center for Protein Research - [PI Jiri Lukas]
  • General Secretariat for Research and Technology - [II-3020]
  • European Commission -
  • Kræftens Bekæmpelse - [R72-A4436]
  • European Molecular Biology Organization -
  • European Research Council - [CRSI33_130016]
Citation (ISO format)
SOTIRIOU, Sotirios et al. Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks. In: Molecular cell, 2016, vol. 64, n° 6, p. 1127–1134. doi: 10.1016/j.molcel.2016.10.038
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Article (Published version)
Identifiers
ISSN of the journal1097-2765
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