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P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation

Oncogene volume 25, pages 2829–2838 (2006)Cite this article

Abstract

p21Cip1/WAF1 is a known inhibitor of the short-gap filling activity of proliferating cell nuclear antigen (PCNA) during DNA repair. In agreement, p21 degradation after UV irradiation promotes PCNA-dependent repair. Recent reports have identified ubiquitination of PCNA as a relevant feature for PCNA-dependent DNA repair. Here, we show that PCNA ubiquitination in human cells is notably augmented after UV irradiation and other genotoxic treatments such as hydroxyurea, aphidicolin and methylmethane sulfonate. Intriguingly, those DNA damaging agents also promoted downregulation of p21. While ubiquitination of PCNA was not affected by deficient nucleotide excision repair (NER) and was observed in both proliferating and arrested cells, stable p21 expression caused a significant reduction in UV-induced ubiquitinated PCNA. Surprisingly, the negative regulation of PCNA ubiquitination by p21 does not depend on the direct interaction with PCNA but requires the cyclin dependent kinase binding domain of p21. Taken together, our data suggest that p21 downregulation plays a role in efficient PCNA ubiquitination after UV irradiation.

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Abbreviations

ActD:

actinomycin D

APH:

aphidicolin

CDK:

cyclin dependent kinase

Dauno:

daunorubicin

DFX:

deferoxamine mesylate

HU:

hydroxyurea

MMS:

methylmethane sulfonate

NER:

Nucleotide excision repair

NCS:

neocarzinostatin

Noc:

nocodazole

PCNA:

proliferating cell nuclear antigen

TLS:

translesion DNA synthesis

BrdU:

5-bromodeoxyuridine

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Acknowledgements

We thank Dr Kristine McKinney and Dr Fernanda Ceriani for helpful suggestions and careful reading of the manuscript. We also thank Marcos Barboza for excellent technical assistance. We are very grateful to Dr S Jentsch, Dr B Clurman and Dr D Turner for advice and plasmids. This work has been supported by grants from Leukemia and Lymphoma Society, Fundación Antorchas, Agencia Nacional de Promoción Cientifica y Tecnológica and CONICET to VG; Fundación Barón to OP and NIH (CA058316) to CP.

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Authors and Affiliations

  1. Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina

    G Soria, O Podhajcer & V Gottifredi

  2. Department of Biological Sciences, Columbia University, New York, NY, USA

    C Prives

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  1. G Soria
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  2. O Podhajcer
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  3. C Prives
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  4. V Gottifredi
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Correspondence to V Gottifredi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Soria, G., Podhajcer, O., Prives, C. et al. P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation. Oncogene 25, 2829–2838 (2006). https://doi.org/10.1038/sj.onc.1209315

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