1. BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage.
- Author
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Kang, Zhihua, Fu, Pan, Alcivar, Allen L, Fu, Haiqing, Redon, Christophe, Foo, Tzeh Keong, Zuo, Yamei, Ye, Caiyong, Baxley, Ryan, Madireddy, Advaitha, Buisson, Remi, Bielinsky, Anja-Katrin, Zou, Lee, Shen, Zhiyuan, Aladjem, Mirit I, and Xia, Bing
- Subjects
BRCA2 Protein ,Cell Line ,Tumor ,Cell Survival ,DNA Damage ,DNA Helicases ,DNA Primase ,DNA Replication ,DNA ,Neoplasm ,DNA ,Single-Stranded ,DNA-Binding Proteins ,DNA-Directed DNA Polymerase ,Gene Expression Regulation ,Neoplastic ,Genomic Instability ,HEK293 Cells ,HeLa Cells ,Humans ,Minichromosome Maintenance Proteins ,Multifunctional Enzymes ,Osteoblasts ,RNA ,Small Interfering ,Recombinational DNA Repair ,Signal Transduction ,Transcription Factors ,Breast Cancer ,Genetics ,Cancer ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning - 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.
- Published
- 2021