期刊
CELL CYCLE
卷 14, 期 15, 页码 2439-2450出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1060381
关键词
chromosome aberrations; DNA resection; exonuclease-1; sumoylation; ubiquitylation
类别
资金
- Swiss National Science Foundation [PDFMP3_127523]
- Hartmann-Muller Foundation
- Swiss Foundation for Fight Against Cancer
- Hermann Foundation
- Huggenberger-Bischoff Foundation
- University of Zurich Research Funds
- Czech Science Foundation [GACR 13- 26629S, 207/12/2323]
- European Regional Development Fund (Project FNUSA-ICRC) [CZ.1.05/1.1.00/02.0123]
- Employment of Newly Graduated Doctors of Science for Scientific Excellence [CZ.1.07/2.3.00/30.0009]
- European Social Fund
- Swiss National Science Foundation (SNF) [PDFMP3_127523] Funding Source: Swiss National Science Foundation (SNF)
DNA double-strand break repair by the error-free pathway of homologous recombination (HR) requires the concerted action of several factors. Among these, EXO1 and DNA2/BLM are responsible for the extensive resection of DNA ends to produce 3'-overhangs, which are essential intermediates for downstream steps of HR. Here we show that EXO1 is a SUMO target and that sumoylation affects EXO1 ubiquitylation and protein stability. We identify an UBC9-PIAS1/PIAS4-dependent mechanism controlling human EXO1 sumoylation in vivo and demonstrate conservation of this mechanism in yeast by the Ubc9-Siz1/Siz2 using an in vitro reconstituted system. Furthermore, we show physical interaction between EXO1 and the de-sumoylating enzyme SENP6 both in vitro and in vivo, promoting EXO1 stability. Finally, we identify the major sites of sumoylation in EXO1 and show that ectopic expression of a sumoylation-deficient form of EXO1 rescues the DNA damage-induced chromosomal aberrations observed upon wt-EXO1 expression. Thus, our study identifies a novel layer of regulation of EXO1, making the pathways that regulate its function an ideal target for therapeutic intervention.
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