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POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis

Marta Llorens-Agost1, Michael Ensminger1, Hang Phuong Le2

  • 1Radiation Biology and DNA Repair, Technical University of Darmstadt, Darmstadt, Germany.

Nature Cell Biology
|October 7, 2021
PubMed

Insights

BRCA2-mutant cells utilize DNA polymerase θ (POLθ)-mediated end joining (TMEJ) for DNA double-strand break (DSB) repair during mitosis. RAD52 regulates this process, preventing premature TMEJ and chromosomal fusions in BRCA2-deficient cells.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • BRCA2-mutant cells exhibit defects in homologous recombination, increasing vulnerability to DNA double-strand break (DSB) repair pathway inactivation.
  • Understanding alternative DSB repair mechanisms in BRCA2-deficient cells is crucial for clinical exploitation of these vulnerabilities.

Purpose of the Study:

  • To elucidate the mechanism of DSB repair in BRCA2-deficient cells, specifically focusing on the role of DNA polymerase θ (POLθ)-mediated end joining (TMEJ).
  • To investigate the regulation of TMEJ by RAD52 and its implications for genomic stability.

Main Methods:

  • Investigated DSB repair pathways in BRCA2-deficient cells.
  • Analyzed the role of RAD52 in regulating TMEJ.
  • Assessed the interaction between RAD52, BRCA2, and POLθ function.

Main Results:

  • TMEJ repairs S-phase DSBs in BRCA2-deficient cells, but only after the onset of mitosis.
  • RAD52 loss leads to premature TMEJ and chromosomal fusions.
  • Both RAD52 and BRCA2 proteins inhibit POLθ polymerase activity, suggesting a synthetic lethal mechanism.

Conclusions:

  • The delay of TMEJ until mitosis is a critical regulatory step in BRCA2-deficient cells, converting one-ended DSBs to two-ended DSBs.
  • Mitotic chromatin condensation may facilitate accurate break end repair and prevent chromosomal fusions.
  • Understanding the interplay between BRCA2, RAD52, and POLθ offers potential therapeutic strategies for BRCA2-mutant cancers.

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