期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 39, 页码 27314-27326出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.578823
关键词
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资金
- Swiss National Science Foundation [31003A-129747, 31003A_146206, PP00P3 133636]
- Czech Science Foundation [GAP305/10/0281]
- Stiftung zur Krebsbekampfung
- Forschungskredit of the University of Zurich [FK-13-098]
- Swiss National Science Foundation (SNF) [PP00P3_133636, 31003A_146206, 31003A_129747] Funding Source: Swiss National Science Foundation (SNF)
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-TOPOIII alpha-RMI1-RMI2 complex. Our study provides new mechanistic insights into the process of DNA end resection in mammalian cells.
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