Homologous recombination resolution defect in werner syndrome.
Werner syndrome (WRN) is an uncommon autosomal recessive disease whose phenotype includes features of premature aging, genetic instability, and an elevated risk of cancer. We used three different experimental strategies to show that WRN cellular phenotypes of limited cell division potential, DNA damage hypersensitivity, and defective homologous recombination (HR) are interrelated. WRN cell survival and the generation of viable mitotic recombinant progeny could be rescued by expressing wild-type WRN protein or by expressing the bacterial resolvase protein RusA. The dependence of WRN cellular phenotypes on RAD51-dependent HR pathways was demonstrated by using a dominant-negative RAD51 protein to suppress mitotic recombination in WRN and control cells: the suppression of RAD51-dependent recombination led to significantly improved survival of WRN cells following DNA damage. These results define a physiological role for the WRN RecQ helicase protein in RAD51-dependent HR and identify a mechanistic link between defective recombination resolution and limited cell division potential, DNA damage hypersensitivity, and genetic instability in human somatic cells.
Saintigny
Yannick
Y
Departments of Pathology. Biostatistics. Genome Sciences, University of Washington, Seattle, Washington 98195-7705, USA.
Makienko
Kate
K
Swanson
Cristina
C
Emond
Mary J
MJ
Monnat
Raymond J
RJ
D002455:Cell Division; D002461:Cell Line, Transformed; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D006801:Humans; D051135:Rad51 Recombinase; D053484:RecQ Helicases; D011995:Recombination, Genetic; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D004268:DNA-Binding Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase