| Autor: |
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., Xia, Bing |
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| Zdroj: |
Nature Communications; 10/13/2021, Vol. 12 Issue 1, p1-12, 12p |
| Abstrakt: |
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. Tumor suppressor BRCA2 is known to stabilize and restart stalled DNA replication forks. Here the authors show that BRCA2 is recruited to the replication fork through its interaction with MCM10 and inhibits Primase-Polymerase-mediated repriming, lesion bypass and single strand DNA gap formation after DNA damage. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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