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: Ana Maria Garcia, Robert N Salomon, Alice Witsell, Justine Liepkalns, R Brent Calder, Moonsook Lee, Martha Lundell, Jan Vijg, Mitch McVey
• Journal: Genome biology (Genome Biol) Vol. 12 Issue 12 Pg. R121 (Dec 19 2011) ISSN: 1474-760X [Electronic] England
• PMID: 22183041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Drosophila Proteins
• DNA Helicases
• blm protein, Drosophila
• DNA Ligases
• DNA Ligase ATP

Topics

• Aging (genetics)
• Animals
• Cell Transformation, Neoplastic (genetics)
• DNA Breaks, Double-Stranded
• DNA Helicases (genetics)
• DNA Ligase ATP
• DNA Ligases (genetics)
• DNA Repair
• Drosophila Proteins
• Drosophila melanogaster (genetics)
• Genes, Reporter
• Genomic Instability
• Lac Operon
• Mutation