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

Haruka Fujimori, Mai Hyodo, Yusuke Matsuno, Atsuhiro Shimizu, Yusuke Minakawa, Yuko Atsumi, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yasufumi Murakami, Ken ichi Yoshioka

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Abstract

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. Biological sciences; Cell biology; Genetics; DNA repair; Molecular biology; Genomic instability; DNA repair; Mismatch repair; Microhomology-mediated end joining; DNA polymerase theta

Original languageEnglish
Article numbere03057
JournalHeliyon
Volume5
Issue number12
DOIs
Publication statusPublished - Dec 2019

All Science Journal Classification (ASJC) codes

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    Fujimori, H., Hyodo, M., Matsuno, Y., Shimizu, A., Minakawa, Y., Atsumi, Y., Nakatsu, Y., Tsuzuki, T., Murakami, Y., & Yoshioka, K. I. (2019). Mismatch repair dependence of replication stress-associated DSB recognition and repair. Heliyon, 5(12), [e03057]. https://doi.org/10.1016/j.heliyon.2019.e03057