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BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage

Zhihua Kang1, Pan Fu1,2, Allen L Alcivar1,3

  • 1Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Nature Communications
|October 14, 2021
PubMed

Insights

BRCA2 deficiency allows DNA replication forks to progress unchecked after damage, primarily due to PRIMPOL repriming, causing gaps. BRCA2

Area of Science:

  • Genetics
  • Molecular Biology
  • DNA Repair

Background:

  • BRCA2 is crucial for genome integrity, DNA repair, and cell cycle checkpoints.
  • BRCA2-deficient cells exhibit radio-resistant DNA synthesis (RDS), but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism behind the RDS phenotype in BRCA2-deficient cells.
  • To investigate BRCA2's role in controlling DNA replication fork progression after DNA damage.

Main Methods:

  • Analysis of DNA replication fork dynamics in BRCA2-deficient cells.
  • Investigating the interaction between BRCA2 and MCM10.
  • Assessing the role of PRIMPOL in DNA gap formation.

Main Results:

  • BRCA2-deficient cells fail to restrain replication fork progression post-damage.
  • PRIMPOL-mediated repriming downstream of lesions causes single-stranded DNA gaps.
  • BRCA2 interacts with MCM10 to suppress PRIMPOL-mediated repriming and ssDNA gap formation.

Conclusions:

  • BRCA2 restrains replication fork progression by suppressing PRIMPOL activity, preventing ssDNA gaps.
  • This function of BRCA2 is critical for genome stability and may impact cancer suppression and therapy response.

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