Site-specific proteolytic cleavage prevents ubiquitination and degradation of human REV3L, the catalytic subunit of DNA polymerase ζ. Issue 7 (17th February 2020)

• Record Type: Journal Article
• Authors: Wang, Fengting; Li, Pan; Shao, Yuan; Li, Yanyan; Zhang, Kai; Li, Miaomiao; Wang, Rong; Zheng, Shuo; Wang, Yingying; Song, Sen; Feng, Shiguo; Liu, Fei; Xiao, Wei; Li, Xialu
• Is Part Of: Nucleic acids research. Volume 48:Issue 7(2020)
• Page Start: 3619
• Page End: 3637
• Publication Date: 2020-02-17
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa096
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: REV3L, the catalytic subunit of DNA polymerase ζ (Pol ζ), is indispensable for translesion DNA synthesis, which protects cells from deleterious DNA lesions resulting from various intrinsic and environmental sources. However, REV3L lacks a proofreading exonuclease activity and consequently bypasses DNA lesions at the expense of increased mutations, which poses a severe threat to genome stability. Here we report a site-specific proteolytic event of human REV3L. We show that REV3L is cleaved by a t hreonine asp artase, Taspase1 (TASP1), to generate an N-terminal 70-kDa fragment (N70) and a polypeptide carrying the C-terminal polymerase catalytic domain in human cells. Strikingly, such a post-translational cleavage event plays a vital role in controlling REV3L stability by preventing ubiquitination and proteasome-mediated degradation of REV3L. Indicative of the biological importance of the above REV3L post-translational processing, cellular responses to UV and cisplatin-induced DNA lesions are markedly impaired in human HCT116 cell derivatives bearing defined point mutations in the endogenous REV3L gene that compromise REV3L cleavage. These findings establish a new paradigm in modulating the abundance of REV3L through site-specific proteolysis in human cells.