TY - JOUR
T1 - Mismatch repair dependence of replication stress-associated DSB recognition and repair
AU - Fujimori, Haruka
AU - Hyodo, Mai
AU - Matsuno, Yusuke
AU - Shimizu, Atsuhiro
AU - Minakawa, Yusuke
AU - Atsumi, Yuko
AU - Nakatsu, Yoshimichi
AU - Tsuzuki, Teruhisa
AU - Murakami, Yasufumi
AU - Yoshioka, Ken ichi
N1 - Funding Information:
This work was supported by was supported by the MEXT / JSPS KAKENHI ( 20770136 ) and the National Cancer Center Research and Development Fund ( 23-C-10 ).
Funding Information:
This work was supported by was supported by the MEXT/JSPS KAKENHI (20770136) and the National Cancer Center Research and Development Fund (23-C-10).
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.heliyon.2019.e03057
DO - 10.1016/j.heliyon.2019.e03057
M3 - Article
AN - SCOPUS:85076441525
SN - 2405-8440
VL - 5
JO - Heliyon
JF - Heliyon
IS - 12
M1 - e03057
ER -
