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

Sotirios K Sotiriou1, Irene Kamileri1, Natalia Lugli1

  • 1Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, 1211 Geneva, Switzerland.

Molecular Cell
|December 17, 2016
PubMed

Insights

Human cancers exhibit DNA replication stress (DRS), relying on pathways like break-induced replication (BIR). RAD52 facilitates the repair of collapsed replication forks in cancer cells, suppressing tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Human cancers frequently experience oncogene-induced DNA replication stress (DRS).
  • Cells with DRS depend on DNA repair pathways, including break-induced replication (BIR), to manage damaged replication forks.
  • RAD52 is a gene not essential for normal development but potentially crucial for DNA repair in cancer.

Purpose of the Study:

  • To identify genes involved in regulating DNA replication stress response pathways.
  • To investigate the role of RAD52 in the repair of collapsed DNA replication forks during oncogene-induced DRS.
  • To evaluate the therapeutic potential of targeting RAD52 in cancer treatment.

Main Methods:

  • Conducted a targeted siRNA screen to identify genes affecting cell cycle progression under oncogenic cyclin E overexpression.
  • Utilized techniques like siRNA depletion and CRISPR/Cas9 gene knockout to study RAD52 function.
  • Observed Rad52 protein localization to DNA replication stress foci.
  • Assessed the impact of RAD52 depletion on the restart of collapsed replication forks and DNA damage.
  • Examined the effect of RAD52 gene deletion on tumor growth and lifespan in cancer-prone mouse models (APC mutant mice).

Main Results:

  • RAD52 was identified as a key gene whose depletion inhibited cell cycle progression during oncogene-induced DRS.
  • Rad52 protein was found to localize to DNA replication stress foci in cells with induced fork collapse.
  • Depletion or knockout of RAD52 impaired the restart of collapsed replication forks and exacerbated DNA damage in cells under DRS.
  • Homozygous deletion of RAD52 suppressed tumor growth and extended lifespan in cancer-prone APC mutant mice.

Conclusions:

  • Mammalian RAD52 plays a significant role in facilitating the repair of collapsed DNA replication forks, particularly in the context of cancer-related DNA replication stress.
  • RAD52 emerges as a potential therapeutic target for suppressing tumor growth in cancers characterized by high levels of DNA replication stress.
Keywords:
DNA recombinationDNA replication stressRAD52break-induced replicationcancer

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