title: Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila.
abstract: 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.
authors.affiliation: Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Garcia
authors.forename: Robert N
authors.initials: RN
authors.lastname: Salomon
authors.forename: Alice
authors.initials: A
authors.lastname: Witsell
authors.forename: Justine
authors.initials: J
authors.lastname: Liepkalns
authors.forename: R Brent
authors.initials: RB
authors.lastname: Calder
authors.forename: Moonsook
authors.initials: M
authors.lastname: Lee
authors.forename: Martha
authors.initials: M
authors.lastname: Lundell
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.forename: Mitch
authors.initials: M
authors.lastname: McVey
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics*; D004260:DNA Repair; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics*; D017930:Genes, Reporter; D042822:Genomic Instability; D007763:Lac Operon; D009154:Mutation
chemical_list: D029721:Drosophila Proteins; D004265:DNA Helicases; C470639:blm protein, Drosophila; D011088:DNA Ligases; D000072481:DNA Ligase ATP