Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila
| Autor: | Martha J. Lundell, R. Brent Calder, Alice Witsell, Moonsook Lee, Robert N. Salomon, Mitch McVey, Justine S. Liepkalns, Ana Maria Garcia, Jan Vijg |
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| Rok vydání: | 2011 |
| Předmět: |
Premature aging
Genome instability congenital hereditary and neonatal diseases and abnormalities Aging DNA Ligases DNA Repair DNA repair Mutagenesis (molecular biology technique) medicine.disease_cause Genomic Instability 03 medical and health sciences DNA Ligase ATP 0302 clinical medicine Genes Reporter medicine Animals Drosophila Proteins Bloom syndrome DNA Breaks Double-Stranded 030304 developmental biology Genetics 0303 health sciences Mutation biology urogenital system Research DNA Helicases Helicase nutritional and metabolic diseases biology.organism_classification medicine.disease Cell Transformation Neoplastic Drosophila melanogaster Lac Operon 030220 oncology & carcinogenesis biology.protein |
| Zdroj: | Genome Biology |
| ISSN: | 1474-760X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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