PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4<sup>Cdt2</sup> ubiquitin ligase complex

Abbas, Tarek; Sivaprasad, Uma; Terai, Kenta; Amador, Virginia; Pagano, Michele; Dutta, Anindya

doi:10.1101/gad.1676108

Cited by 347 publications

(415 citation statements)

References 34 publications

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“…This has been resolved by the findings of the involvement of ATR and CRL4 Cdt2 , which regulate the UV-induced degradation of p21 (reviewed in Soria and Gottifredi [2010]). p21 levels also change during cell-cycle progression under the regulation of the CRL4 Cdt2 ubiquitin system [Kim et al, 2008], which regulates the degradation of the licensing factors Cdt1 and Set8 during S phase to prevent rereplication [Abbas et al, 2008;Havens and Walter, 2011]. These observations are consistent with the results from our laboratory showing that p12 levels appear to decrease during S phase [Chea et al, 2012].…”

Section: Connections Between P12 and P21çp21as A Regulator Of Pol D Asupporting

confidence: 90%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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The p12 subunit of polymerase delta (Pol d) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol d4 holoenzyme to the heterotrimer, Pol d3. We review studies that establish that Pol d3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol d3 exhibits properties of an ''antimutator'' polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol d carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol d to sites of DNA damage show that Pol d3 is the primary form of Pol d associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol d engaged in DNA repair. We propose a model for the switching of Pol d with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol d3. Because of the critical role of Pol d activity in DNA replication and repair, the formation of Pol d3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Environ. Mol. Mutagen. 53:683-698, 2012. V V C 2012 Wiley Periodicals, Inc.

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Section: Connections Between P12 and P21çp21as A Regulator Of Pol D Asupporting

confidence: 90%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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“…A p21 CIP1 mutant that cannot be degraded following damage remains associated with PCNA and blocks docking of the translesion synthesis polymerase Pol-η (22). Unlike p21 CIP1 , which is degraded by the ubiquitin E3 ligase CRL4-Cdt2 following DNA damage (23, 24), we did not detect a change in PAF15 levels following treatment with UV, IR, mitomycin C, and hydroxyurea, suggesting that PAF15 differs from p21/CIP1 in response to DNA damage (23). Additionally, although PAF15 and PCNA appear to interact in a 1:1 complex, because PCNA forms a trimer we cannot formally exclude the possibility that a fraction of PAF15 interacts with intact PCNA trimers.…”

Section: Paf15mentioning

confidence: 40%

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

Emanuele

Ciccia

Elia

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

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The anaphase-promoting complex/cyclosome (APC/C) is a cell cycleregulated E3 ubiquitin ligase that controls the degradation of substrate proteins at mitotic exit and throughout the G1 phase. We have identified an APC/C substrate and cell cycle-regulated protein, KIAA0101/PAF15. PAF15 protein levels peak in the G2/M phase of the cell cycle and drop rapidly at mitotic exit in an APC/C-and KEN-box-dependent fashion. PAF15 associates with proliferating cell nuclear antigen (PCNA), and depletion of PAF15 decreases the number of cells in S phase, suggesting a role for it in cell cycle regulation. Following irradiation, PAF15 colocalized with γH2AX foci at sites of DNA damage through its interaction with PCNA. Finally, PAF15 depletion led to an increase in homologous recombinationmediated DNA repair, and overexpression caused sensitivity to UV-induced DNA damage. We conclude that PAF15 is an APC/Cregulated protein involved in both cell cycle progression and the DNA damage response.DNA replication | proteolysis

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“…Cdt2 also targets the histone methyltransferase Set8 (7,8) and the cyclin-dependent kinase inhibitor p21 (9,10). In both cases, destruction is thought to inhibit licensing in S phase.…”

Section: Crl4mentioning

confidence: 99%

Thymine DNA Glycosylase Is a CRL4Cdt2 Substrate

Slenn

Morris

Havens

et al. 2014

Journal of Biological Chemistry

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Background: E3 ubiquitin ligases facilitate destruction of other proteins. Results: In frog egg extract, the DNA repair factor thymine DNA glycosylase (TDG) was destroyed during DNA replication and repair, dependent on the E3 ubiquitin ligase CRL4 Cdt2 . Conclusion: TDG is a novel target of CRL4 Cdt2 . Significance: We identified a novel form of TDG regulation that informs how cells regulate S phase and epigenetic inheritance.

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PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4^Cdt2 ubiquitin ligase complex

Abstract: [Keywords: CRL4; DDB1; PCNA; p21 ubiquitylation; Cdt2; DCAFs] Supplemental material is available at http://www.genesdev.org.

Cited by 347 publications

References 34 publications

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

Thymine DNA Glycosylase Is a CRL4Cdt2 Substrate

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PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex

Abstract: [Keywords: CRL4; DDB1; PCNA; p21 ubiquitylation; Cdt2; DCAFs] Supplemental material is available at http://www.genesdev.org.

Cited by 347 publications

References 34 publications

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

Thymine DNA Glycosylase Is a CRL4Cdt2 Substrate

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Resources

About

PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4^Cdt2 ubiquitin ligase complex