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

Zhihua Kang, Pan Fu, Allen L. Alcivar, Haiqing Fu, Christophe Redon, Tzeh Keong Foo, Yamei Zuo, Caiyong Ye, Ryan Baxley, Advaitha Madireddy, Remi Buisson, Anja-Katrin Bielinsky, Lee Zou, Zhiyuan Shen, Mirit I. Aladjem and Bing Xia ()
Additional contact information
Zhihua Kang: Rutgers Cancer Institute of New Jersey
Pan Fu: Rutgers Cancer Institute of New Jersey
Allen L. Alcivar: Rutgers Cancer Institute of New Jersey
Haiqing Fu: National Cancer Institute
Christophe Redon: National Cancer Institute
Tzeh Keong Foo: Rutgers Cancer Institute of New Jersey
Yamei Zuo: Rutgers Cancer Institute of New Jersey
Caiyong Ye: Rutgers Cancer Institute of New Jersey
Ryan Baxley: University of Minnesota
Advaitha Madireddy: Rutgers Cancer Institute of New Jersey
Remi Buisson: Massachusetts General Hospital Cancer Center and Harvard Medical School
Anja-Katrin Bielinsky: University of Minnesota
Lee Zou: Massachusetts General Hospital Cancer Center and Harvard Medical School
Zhiyuan Shen: Rutgers Cancer Institute of New Jersey
Mirit I. Aladjem: National Cancer Institute
Bing Xia: Rutgers Cancer Institute of New Jersey

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resistant DNA synthesis (RDS) phenotype, however the mechanism has remained elusive. Here we show that cells without BRCA2 are unable to sufficiently restrain DNA replication fork progression after DNA damage, and the underrestrained fork progression is due primarily to Primase-Polymerase (PRIMPOL)-mediated repriming of DNA synthesis downstream of lesions, leaving behind single-stranded DNA gaps. Moreover, we find that BRCA2 associates with the essential DNA replication factor MCM10 and this association suppresses PRIMPOL-mediated repriming and ssDNA gap formation, while having no impact on the stability of stalled replication forks. Our findings establish an important function for BRCA2, provide insights into replication fork control during the DNA damage response, and may have implications in tumor suppression and therapy response.

Date: 2021
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DOI: 10.1038/s41467-021-26227-6

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