%0 Journal Article
%T Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila
%A Ana Garcia
%A Robert N Salomon
%A Alice Witsell
%A Justine Liepkalns
%A R Brent Calder
%A Moonsook Lee
%A Martha Lundell
%A Jan Vijg
%A Mitch McVey
%J Genome Biology
%D 2011
%I BioMed Central
%R 10.1186/gb-2011-12-12-r121
%X 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.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.Bloom syndrome is a rare, autosomal recessive disorder whose most striking characteristic is a predisposition to all types of cancers (reviewed in [1,2]). It is caused by mutations in the BLM gene, a member of the RecQ family of DNA helicases [3]. Cells derived from Bloom syndrome patients and Blm hypomorphic mice exhibit greatly elevated genome instability, including a dramatically increased frequency of sister chromatid exchanges [4,5].Cells with defective BLM also have a heightened mutation frequency that is partially independent of the increase in sister chromatid exchanges [6-9]. 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. 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 mus309 gene encodes the Drosophila melanogaster BLM ortholog DmBlm [10]. Flies lacking DmBlm phenocopy many of the characteri
%U http://genomebiology.com/2011/12/12/R121