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Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila
BACKGROUND: The BLM DNA helicase plays a vital role in maintaining genome stability. Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the mol...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334616/ https://www.ncbi.nlm.nih.gov/pubmed/22183041 http://dx.doi.org/10.1186/gb-2011-12-12-r121 |
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author | Garcia, Ana Maria Salomon, Robert N Witsell, Alice Liepkalns, Justine Calder, R Brent Lee, Moonsook Lundell, Martha Vijg, Jan McVey, Mitch |
author_facet | Garcia, Ana Maria Salomon, Robert N Witsell, Alice Liepkalns, Justine Calder, R Brent Lee, Moonsook Lundell, Martha Vijg, Jan McVey, Mitch |
author_sort | Garcia, Ana Maria |
collection | PubMed |
description | BACKGROUND: The BLM DNA helicase plays a vital role in maintaining genome stability. Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the molecular basis of this increase is not well understood. In addition, the effect of aging on spontaneous mutagenesis in blm mutants has not been characterized. To address this, we used a lacZ reporter system in wild-type and several mutant strains of Drosophila melanogaster to analyze mechanisms of mutagenesis throughout their lifespan. RESULTS: Our data show that Drosophila lacking BLM have an elevated frequency of spontaneous genome rearrangements that increases with age. Although in normal flies most genome rearrangements occur through DNA ligase 4-dependent classical end joining, most rearrangements that accumulate during aging in blm mutants do not require DNA ligase 4, suggesting the influence of an alternative end-joining mechanism. Adult blm mutants also display reduced lifespan and ligase 4-independent enhanced tumorigenesis in mitotically active tissues. CONCLUSIONS: These results suggest that Drosophila BLM suppresses error-prone alternative end-joining repair of DNA double-strand breaks that can result in genome instability and tumor formation during aging. In addition, since loss of BLM significantly affects lifespan and tumorigenesis, the data provide a link between error-prone end joining, genome rearrangements, and tumor formation in a model metazoan. |
format | Online Article Text |
id | pubmed-3334616 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-33346162012-04-25 Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila Garcia, Ana Maria Salomon, Robert N Witsell, Alice Liepkalns, Justine Calder, R Brent Lee, Moonsook Lundell, Martha Vijg, Jan McVey, Mitch Genome Biol Research BACKGROUND: The BLM DNA helicase plays a vital role in maintaining genome stability. Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the molecular basis of this increase is not well understood. In addition, the effect of aging on spontaneous mutagenesis in blm mutants has not been characterized. To address this, we used a lacZ reporter system in wild-type and several mutant strains of Drosophila melanogaster to analyze mechanisms of mutagenesis throughout their lifespan. RESULTS: Our data show that Drosophila lacking BLM have an elevated frequency of spontaneous genome rearrangements that increases with age. Although in normal flies most genome rearrangements occur through DNA ligase 4-dependent classical end joining, most rearrangements that accumulate during aging in blm mutants do not require DNA ligase 4, suggesting the influence of an alternative end-joining mechanism. Adult blm mutants also display reduced lifespan and ligase 4-independent enhanced tumorigenesis in mitotically active tissues. CONCLUSIONS: These results suggest that Drosophila BLM suppresses error-prone alternative end-joining repair of DNA double-strand breaks that can result in genome instability and tumor formation during aging. In addition, since loss of BLM significantly affects lifespan and tumorigenesis, the data provide a link between error-prone end joining, genome rearrangements, and tumor formation in a model metazoan. BioMed Central 2011 2011-12-19 /pmc/articles/PMC3334616/ /pubmed/22183041 http://dx.doi.org/10.1186/gb-2011-12-12-r121 Text en Copyright ©2011 Garcia et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Garcia, Ana Maria Salomon, Robert N Witsell, Alice Liepkalns, Justine Calder, R Brent Lee, Moonsook Lundell, Martha Vijg, Jan McVey, Mitch Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila |
title | Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila |
title_full | Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila |
title_fullStr | Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila |
title_full_unstemmed | Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila |
title_short | Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila |
title_sort | loss of the bloom syndrome helicase increases dna ligase 4-independent genome rearrangements and tumorigenesis in aging drosophila |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334616/ https://www.ncbi.nlm.nih.gov/pubmed/22183041 http://dx.doi.org/10.1186/gb-2011-12-12-r121 |
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