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Cell Cycle. 2016 Dec 16;15(24):3390-3401. doi: 10.1080/15384101.2016.1245247. Epub 2016 Oct 18.

PCNA-Ub polyubiquitination inhibits cell proliferation and induces cell-cycle checkpoints.

Qin Z1,2, Bai Z1, Sun Y1, Niu X1, Xiao W1,2.

Author information

1
a College of Life Sciences, Capital Normal University , Beijing China.
2
b Department of Microbiology and Immunology , University of Saskatchewan , Saskatoon , SK , Canada.

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.

KEYWORDS:

ATR; DNA-damage tolerance; DSB; PCNA; cell cycle checkpoint; polyubiquitination

PMID:
27753536
PMCID:
PMC5224464
DOI:
10.1080/15384101.2016.1245247
[Indexed for MEDLINE]
Free PMC Article

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