title: 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.
authors.affiliation: a College of Life Sciences, Capital Normal University , Beijing China.|b Department of Microbiology and Immunology , University of Saskatchewan , Saskatoon , SK , Canada.
authors.forename: Zhoushuai
authors.initials: Z
authors.lastname: Qin
authors.affiliation: a College of Life Sciences, Capital Normal University , Beijing China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Bai
authors.affiliation: a College of Life Sciences, Capital Normal University , Beijing China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: a College of Life Sciences, Capital Normal University , Beijing China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Niu
authors.affiliation: a College of Life Sciences, Capital Normal University , Beijing China.|b Department of Microbiology and Immunology , University of Saskatchewan , Saskatoon , SK , Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D016923:Cell Death; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008954:Models, Biological; D025821:Polyubiquitin / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D015398:Signal Transduction; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004277:DNA, Single-Stranded; D018809:Proliferating Cell Nuclear Antigen; D000071857:Tumor Suppressor p53-Binding Protein 1; D025821:Polyubiquitin; D064007:Ataxia Telangiectasia Mutated Proteins; D008239:Lysine
keywords: ATR; DNA-damage tolerance; DSB; PCNA; cell cycle checkpoint; polyubiquitination