Sumoylation regulates EXO1 stability and processing of DNA damage

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Authors

BOLOGNA Serena ALTMANNOVÁ Veronika VALTORTA Emanuele KOENIG Christiane LIBERALI Prisca GENTILI Christian ANRATHER Dorothea AMMERER Gustav PELKMANS Lucas KREJČÍ Lumír FERRARI Stefano

Year of publication 2015
Type Article in Periodical
Magazine / Source Cell Cycle
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1080/15384101.2015.1060381
Field Genetics and molecular biology
Keywords chromosome aberrations; DNA resection; exonuclease-1; sumoylation; ubiquitylation
Description 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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