DNA-damage-induced degradation of EXO1 exonuclease limits DNA end resection to ensure accurate DNA repair.

The Journal of Biological Chemistry
Nozomi TomimatsuSandeep Burma

Abstract

End resection of DNA double-strand breaks (DSBs) to generate 3'-single-stranded DNA facilitates DSB repair via error-free homologous recombination (HR) while stymieing repair by the error-prone non-homologous end joining (NHEJ) pathway. Activation of DNA end resection involves phosphorylation of the 5' to 3' exonuclease EXO1 by the phosphoinositide 3-kinase-like kinases ATM (ataxia telangiectasia-mutated) and ATR (ATM and Rad3-related) and by the cyclin-dependent kinases 1 and 2. After activation, EXO1 must also be restrained to prevent over-resection that is known to hamper optimal HR and trigger global genomic instability. However, mechanisms by which EXO1 is restrained are still unclear. Here, we report that EXO1 is rapidly degraded by the ubiquitin-proteasome system soon after DSB induction in human cells. ATR inhibition attenuated DNA-damage-induced EXO1 degradation, indicating that ATR-mediated phosphorylation of EXO1 targets it for degradation. In accord with these results, EXO1 became resistant to degradation when its SQ motifs required for ATR-mediated phosphorylation were mutated. We show that upon the induction of DNA damage, EXO1 is ubiquitinated by a member of the Skp1-Cullin1-F-box (SCF) family of ubiquitin ligase...Continue Reading

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Citations

Aug 9, 2019·The EMBO Journal·Michael Charles LanzMarcus Bustamante Smolka
Aug 12, 2018·Current Genetics·Hélène Bordelet, Karine Dubrana
Oct 22, 2019·Frontiers in Physiology·Shahd FouadVincenzo D'Angiolella
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Oct 31, 2020·Experimental & Molecular Medicine·Fei ZhaoZhenkun Lou
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Dec 2, 2020·Progress in Biophysics and Molecular Biology·Rhys M Williams, Xiaodong Zhang
Apr 23, 2021·Progress in Biophysics and Molecular Biology·Rhys M Williams, Xiaodong Zhang
Aug 7, 2021·Genes·Marcelina W Musiałek, Dorota Rybaczek
Jul 21, 2021·International Journal of Radiation Biology·Jac A NickoloffRobert Hromas
Jun 4, 2019·Molecular Cell·Michael M SoniatIlya J Finkelstein

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