![]() Although initiation of homologous recombination is required for the deletions observed in blm mutants, the molecular mechanisms responsible for deletion formation remain unknown. In its absence, DSB repair frequently proceeds through non-conservative, deletion-prone repair mechanisms. DmBlm is required for accurate homologous recombination (HR) repair of site-specific DNA double-strand breaks (DSBs) and for prevention of mitotic crossovers. Flies lacking DmBlm phenocopy many of the characteristics of human Bloom syndrome, including reduced fertility and increased mitotic sister chromatid exchanges. The mus309 gene encodes the Drosophila melanogaster BLM ortholog DmBlm. Because these types of mutations are hypothesized to be driving forces in the development and progression of cancer in Bloom syndrome patients, understanding their origin is important. The cause of this is poorly understood, but it may be related to the increased number of chromosome aberrations and translocations that are observed in BLM mutant cells. Ĭells with defective BLM also have a heightened mutation frequency that is partially independent of the increase in sister chromatid exchanges. Cells derived from Bloom syndrome patients and Blm hypomorphic mice exhibit greatly elevated genome instability, including a dramatically increased frequency of sister chromatid exchanges. It is caused by mutations in the BLM gene, a member of the RecQ family of DNA helicases. 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.īloom syndrome is a rare, autosomal recessive disorder whose most striking characteristic is a predisposition to all types of cancers (reviewed in ). 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. Adult blm mutants also display reduced lifespan and ligase 4-independent enhanced tumorigenesis in mitotically active tissues. 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. Our data show that Drosophila lacking BLM have an elevated frequency of spontaneous genome rearrangements that increases with age. 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. In addition, the effect of aging on spontaneous mutagenesis in blm mutants has not been characterized. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the molecular basis of this increase is not well understood. ![]() Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. The BLM DNA helicase plays a vital role in maintaining genome stability.
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