PCNA-Ub polyubiquitination inhibits cell proliferation and induces cell-cycle checkpoints. Issue 24 (16th December 2016)

• Record Type: Journal Article
• Authors: Qin, Zhoushuai; Bai, Zhiqiang; Sun, Ying; Niu, Xiaohong; Xiao, Wei
• Is Part Of: Cell cycle. Volume 15:Issue 24(2016)
• Page Start: 3390
• Page End: 3401
• Publication Date: 2016-12-16
• Subjects: ATR -- cell cycle checkpoint -- DNA-damage tolerance -- DSB -- PCNA -- polyubiquitination; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2016.1245247
• Languages: English
• ISSNs: 1538-4101

Abstract

ABSTRACT: In response to replication-blocking lesions, proliferating cell nuclear antigen (PCNA) can be sequentially ubiquitinated at the K164 residue leading to 2 modes of DNA-damage tolerance, namely translesion DNA synthesis (TLS) and error-free lesion bypass. Ectopic expression of PCNA fused with ubiquitin (Ub) lacking the 2 C-terminal Gly residues resembles PCNA monoubiquitination-mediated TLS. However, if the fused Ub contains C-terminal Gly residues, it is further polyubiquitinated and inhibits cell proliferation. Unexpectedly, the polyubiquitination chain does not require any surface Lys residues and is likely to be head-to-tail linked. Such PCNA polyubiquitination interferes with replication, arrests cells at the S-phase and activates the p53 checkpoint pathway. The above cell-cycle arrest is reversible in an ATR-dependent manner, as simultaneous inhibition of ATR, but not ATM, induces apoptosis. Since ectopic expression of PCNA-Ub also induces double-strand breaks that colocalize with single-stranded DNA, we infer that this non-canonical PCNA poly-Ub chain serves as a signal to activate ATR checkpoint and recruit double-strand-break repair apparatus.