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

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.

SUBMITTER: Qin Z

PROVIDER: S-EPMC5224464 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Qin Zhoushuai Z Bai Zhiqiang Z Sun Ying Y Niu Xiaohong X Xiao Wei W

Cell cycle (Georgetown, Tex.) 20161018 24

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 cel ...[more]

PMID: 27753536

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

Publications

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

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