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PLoS Genet. 2018 Nov 29;14(11):e1007816. doi: 10.1371/journal.pgen.1007816. eCollection 2018 Nov.

BLM prevents instability of structure-forming DNA sequences at common fragile sites.

Author information

1
Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing, China.
2
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States of America.

Abstract

Genome instability often arises at common fragile sites (CFSs) leading to cancer-associated chromosomal rearrangements. However, the underlying mechanisms of how CFS protection is achieved is not well understood. We demonstrate that BLM plays an important role in the maintenance of genome stability of structure-forming AT-rich sequences derived from CFSs (CFS-AT). BLM deficiency leads to increased DSB formation and hyper mitotic recombination at CFS-AT and induces instability of the plasmids containing CFS-AT. We further showed that BLM is required for suppression of CFS breakage upon oncogene expression. Both helicase activity and ATR-mediated phosphorylation of BLM are important for preventing genetic instability at CFS-AT sequences. Furthermore, the role of BLM in protecting CFS-AT is not epistatic to that of FANCM, a translocase that is involved in preserving CFS stability. Loss of BLM helicase activity leads to drastic decrease of cell viability in FANCM deficient cells. We propose that BLM and FANCM utilize different mechanisms to remove DNA secondary structures forming at CFS-AT on replication forks, thereby preventing DSB formation and maintaining CFS stability.

PMID:
30496191
PMCID:
PMC6289451
DOI:
10.1371/journal.pgen.1007816
[Indexed for MEDLINE]
Free PMC Article

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