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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.

Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila