Mismatch repair dependence of replication stress-associated DSB recognition and repair

Heliyon

Atsuhiro Shimizu¹  Yasufumi Murakami¹  Mai Hyodo¹  Yuko Atsumi²  Yusuke Minakawa³  Teruhisa Tsuzuki³  Yoshimichi Nakatsu³  Yusuke Matsuno³  Haruka Fujimori³  Ken-ichi Yoshioka³ 

[1] Biological Science and Technology, Tokyo University of Science, 6-1-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan;Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan;Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan;

关键词: Biological sciences;    Cell biology;    Genetics;    DNA repair;    Molecular biology;    Genomic instability;   

DOI  :  

来源: DOAJ

【 摘 要 】

Most cancers develop with one of two types of genomic instability, namely, chromosomal instability (CIN) or microsatellite instability (MSI). Both are induced by replication stress-associated DNA double-strand breaks (DSBs). The type of genomic instability that arises is dependent on the choice of DNA repair pathway. Specifically, MSI is induced via a PolQ-dependent repair pathway called microhomology-mediated end joining (MMEJ) in a mismatch repair (MMR)-deficient background. However, it is unclear how the MMR status determines the choice of DSB repair pathway. Here, we show that replication stress-associated DSBs initially targeted by the homologous recombination (HR) system were subsequently hijacked by PolQ-dependent MMEJ in MMR-deficient cells, but persisted as HR intermediates in MMR-proficient cells. PolQ interacting with MMR factors was effectively loaded onto damaged chromatin in an MMR-deficient background, in which merged MRE11/γH2AX foci also effectively formed. Thus, the choice of DNA repair pathway according to the MMR status determines whether CIN or MSI is induced.

【 授权许可】

Unknown