Multiple functions of Drosophila BLM helicase in maintenance of genome stability.
Bloom Syndrome, a rare human disorder characterized by genomic instability and predisposition to cancer, is caused by mutation of BLM, which encodes a RecQ-family DNA helicase. The Drosophila melanogaster ortholog of BLM, DmBlm, is encoded by mus309. Mutations in mus309 cause hypersensitivity to DNA-damaging agents, female sterility, and defects in repairing double-strand breaks (DSBs). To better understand these phenotypes, we isolated novel mus309 alleles. Mutations that delete the N terminus of DmBlm, but not the helicase domain, have DSB repair defects as severe as those caused by null mutations. We found that female sterility is due to a requirement for DmBlm in early embryonic cell cycles; embryos lacking maternally derived DmBlm have anaphase bridges and other mitotic defects. These defects were less severe for the N-terminal deletion alleles, so we used one of these mutations to assay meiotic recombination. Crossovers were decreased to about half the normal rate, and the remaining crossovers were evenly distributed along the chromosome. We also found that spontaneous mitotic crossovers are increased by several orders of magnitude in mus309 mutants. These results demonstrate that DmBlm functions in multiple cellular contexts to promote genome stability.
McVey
Mitch
M
Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Andersen
Sabrina L
SL
Broze
Yuri
Y
Sekelsky
Jeff
J
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001816:Bloom Syndrome / Q000201:enzymology / Q000235:genetics; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000196:embryology / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D017344:Genes, Insect; D042822:Genomic Instability; D006801:Humans; D007247:Infertility, Female / Q000201:enzymology / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics; D008938:Mitosis / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D017434:Protein Structure, Tertiary; D053484:RecQ Helicases; D011995:Recombination, Genetic; D017384:Sequence Deletion
D029721:Drosophila Proteins; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; C470639:blm protein, Drosophila