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

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...

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Autores principales: Wang, Hailong, Li, Shibo, Zhang, Huimin, Wang, Ya, Hao, Shuailin, Wu, Xiaohua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289451/
https://www.ncbi.nlm.nih.gov/pubmed/30496191
http://dx.doi.org/10.1371/journal.pgen.1007816
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author Wang, Hailong
Li, Shibo
Zhang, Huimin
Wang, Ya
Hao, Shuailin
Wu, Xiaohua
author_facet Wang, Hailong
Li, Shibo
Zhang, Huimin
Wang, Ya
Hao, Shuailin
Wu, Xiaohua
author_sort Wang, Hailong
collection PubMed
description 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.
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spelling pubmed-62894512018-12-28 BLM prevents instability of structure-forming DNA sequences at common fragile sites Wang, Hailong Li, Shibo Zhang, Huimin Wang, Ya Hao, Shuailin Wu, Xiaohua PLoS Genet Research Article 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. Public Library of Science 2018-11-29 /pmc/articles/PMC6289451/ /pubmed/30496191 http://dx.doi.org/10.1371/journal.pgen.1007816 Text en © 2018 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wang, Hailong
Li, Shibo
Zhang, Huimin
Wang, Ya
Hao, Shuailin
Wu, Xiaohua
BLM prevents instability of structure-forming DNA sequences at common fragile sites
title BLM prevents instability of structure-forming DNA sequences at common fragile sites
title_full BLM prevents instability of structure-forming DNA sequences at common fragile sites
title_fullStr BLM prevents instability of structure-forming DNA sequences at common fragile sites
title_full_unstemmed BLM prevents instability of structure-forming DNA sequences at common fragile sites
title_short BLM prevents instability of structure-forming DNA sequences at common fragile sites
title_sort blm prevents instability of structure-forming dna sequences at common fragile sites
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289451/
https://www.ncbi.nlm.nih.gov/pubmed/30496191
http://dx.doi.org/10.1371/journal.pgen.1007816
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