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

doi:10.1016/j.heliyon.2019.e03057

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

Heliyon. 2019 Dec 24;5(12):e03057. doi: 10.1016/j.heliyon.2019.e03057. eCollection 2019 Dec.

Authors

Haruka Fujimori^{1

2}, Mai Hyodo^{1

2}, Yusuke Matsuno^{1

3}, Atsuhiro Shimizu¹, Yusuke Minakawa^{1

2}, Yuko Atsumi¹, Yoshimichi Nakatsu⁴, Teruhisa Tsuzuki⁴, Yasufumi Murakami², Ken-Ichi Yoshioka¹

Affiliations

¹ Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
² Biological Science and Technology, Tokyo University of Science, 6-1-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
³ Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan.
⁴ Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

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.

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