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DNA2 Cooperates with the WRN and BLM RecQ Helicases to Mediate Long-range DNA End Resection in Human Cells
Authors:Andreas Sturzenegger  Kamila Burdova  Radhakrishnan Kanagaraj  Maryna Levikova  Cosimo Pinto  Petr Cejka  Pavel Janscak
Institution:From the Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland and ;the §Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14300 Prague, Czech Republic
Abstract:The 5′-3′ resection of DNA ends is a prerequisite for the repair of DNA double strand breaks by homologous recombination, microhomology-mediated end joining, and single strand annealing. Recent studies in yeast have shown that, following initial DNA end processing by the Mre11-Rad50-Xrs2 complex and Sae2, the extension of resection tracts is mediated either by exonuclease 1 or by combined activities of the RecQ family DNA helicase Sgs1 and the helicase/endonuclease Dna2. Although human DNA2 has been shown to cooperate with the BLM helicase to catalyze the resection of DNA ends, it remains a matter of debate whether another human RecQ helicase, WRN, can substitute for BLM in DNA2-catalyzed resection. Here we present evidence that WRN and BLM act epistatically with DNA2 to promote the long-range resection of double strand break ends in human cells. Our biochemical experiments show that WRN and DNA2 interact physically and coordinate their enzymatic activities to mediate 5′-3′ DNA end resection in a reaction dependent on RPA. In addition, we present in vitro and in vivo data suggesting that BLM promotes DNA end resection as part of the BLM-TOPOIIIα-RMI1-RMI2 complex. Our study provides new mechanistic insights into the process of DNA end resection in mammalian cells.
Keywords:DNA Damage  DNA Helicase  DNA Recombination  DNA Repair  Genomic Instability  RecQ
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