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

Publikation: Bidrag til tidsskriftTidsskriftartikel

  • Sotirios K Sotiriou
  • Irene Kamileri
  • Natalia Lugli
  • Konstantinos Evangelou
  • Caterina Da-Ré
  • Florian Huber
  • Laura Padayachy
  • Sebastien Tardy
  • Noemie L Nicati
  • Samia Barriot
  • Fena Ochs
  • Lukas, Claudia
  • Lukas, Jiri
  • Vassilis G Gorgoulis
  • Leonardo Scapozza
  • Thanos D Halazonetis

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.

OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind64
Udgave nummer6
Sider (fra-til)1127-1134
Antal sider8
ISSN1097-2765
DOI
StatusUdgivet - 15 dec. 2016

ID: 172394498