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Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions.

Authors :
Sinha, Supriya
Li, Fuyang
Villarreal, Diana
Shim, Jae Hoon
Yoon, Suhyeon
Myung, Kyungjae
Shim, Eun Yong
Lee, Sang Eun
Source :
PLoS Genetics; 4/18/2017, Vol. 13 Issue 4, p1-25, 25p
Publication Year :
2017

Abstract

Microhomology (MH) flanking a DNA double-strand break (DSB) drives chromosomal rearrangements but its role in mutagenesis has not yet been analyzed. Here we determined the mutation frequency of a URA3 reporter gene placed at multiple locations distal to a DSB, which is flanked by different sizes (15-, 18-, or 203-bp) of direct repeat sequences for efficient repair in budding yeast. Induction of a DSB accumulates mutations in the reporter gene situated up to 14-kb distal to the 15-bp MH, but more modestly to those carrying 18- and 203-bp or no homology. Increased mutagenesis in MH-mediated end joining (MMEJ) appears coupled to its slower repair kinetics and the extensive resection occurring at flanking DNA. Chromosomal translocations via MMEJ also elevate mutagenesis of the flanking DNA sequences 7.1 kb distal to the breakpoint junction as compared to those without MH. The results suggest that MMEJ could destabilize genomes by triggering structural alterations and increasing mutation burden. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15537390
Volume :
13
Issue :
4
Database :
Complementary Index
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
122559050
Full Text :
https://doi.org/10.1371/journal.pgen.1006714