Journal
GENES & DEVELOPMENT
Volume 32, Issue 7-8, Pages 524-536Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.311084.117
Keywords
chromosomal rearrangement; homologous recombination; repeat divergence; MSH2; KU70; BRCA1
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Funding
- National Cancer Institute of the National Institutes of Health [R01CA120954, R01CA197506, P30CA33572]
- Ford Foundation Predoctoral Fellowship
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Chromosomal deletion rearrangements mediated by repetitive elements often involve repeats separated by several kilobases and sequences that are divergent. While such rearrangements are likely induced by DNA double-strand breaks (DSBs), it has been unclear how the proximity of DSBs relative to repeat sequences affects the frequency of such events. We generated a reporter assay in mouse cells for a deletion rearrangement involving repeats separated by 0.4 Mb. We induced this repeat-mediated deletion (RMD) rearrangement with two DSBs: the 5 ' DSB that is just downstream fromthe first repeat and the 3 ' DSB that is varying distances upstream of the second repeat. Strikingly, we found that increasing the 3 ' DSB/repeat distance from 3.3 kb to 28.4 kb causes only a modest decrease in rearrangement frequency. We also found that RMDs are suppressed by KU70 and RAD51 and promoted by RAD52, CtIP, and BRCA1. In addition, we found that 1%-3% sequence divergence substantially suppresses these rearrangements in a manner dependent on the mismatch repair factor MSH2, which is dominant over the suppressive role of KU70. We suggest that a DSB far from a repeat can stimulate repeat-mediated rearrangements, but multiple pathways suppress these events.
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