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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6 Citations (Scopus)


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.

Original languageEnglish
Article numbere03057
Issue number12
Publication statusPublished - Dec 2019

All Science Journal Classification (ASJC) codes

  • General


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