Journal
HELIYON
Volume 5, Issue 12, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.heliyon.2019.e03057
Keywords
Biological sciences; Cell biology; Genetics; DNA repair; Molecular biology; Genomic instability; Mismatch repair; Microhomology-mediated end joining; DNA polymerase theta
Categories
Funding
- MEXT/JSPS KAKENHI [20770136]
- National Cancer Center Research and Development Fund [23-C-10]
- Grants-in-Aid for Scientific Research [20770136] Funding Source: KAKEN
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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/gamma H2AX 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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