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First published online 21 March 2006
doi: 10.1242/jcs.02868

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Spatiotemporal dynamics of p21^CDKN1A protein recruitment to DNA-damage sites and interaction with proliferating cell nuclear antigen

¹ Dipartimento di Medicina Sperimentale, sez. Patologia generale, Università di Pavia, 27100 Pavia, Italy
² Ludwig Maximilians University Munich, Department of Biology II, 82152 Planegg-Martinsried, Germany
³ Istituto di Genetica Molecolare-CNR, sez. Istochimica e Citometria, Dipartimento di Biologia Animale, Università di Pavia, 27100 Pavia, Italy
⁴ Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany

^* Author for correspondence (e-mail: prosperi{at}igm.cnr.it)

Accepted 4 January 2006

The cyclin-dependent kinase inhibitor p21^CDKN1A plays a fundamental role in the DNA-damage response by inducing cell-cycle arrest, and by inhibiting DNA replication through association with the proliferating cell nuclear antigen (PCNA). However, the role of such an interaction in DNA repair is poorly understood and controversial. Here, we provide evidence that a pool of p21 protein is rapidly recruited to UV-induced DNA-damage sites, where it colocalises with PCNA and PCNA-interacting proteins involved in nucleotide excision repair (NER), such as DNA polymerase , XPG and CAF-1. In vivo imaging and confocal fluorescence microscopy analysis of cells coexpressing p21 and PCNA fused to green or red fluorescent protein (p21-GFP, RFP-PCNA), showed a rapid relocation of both proteins at microirradiated nuclear spots, although dynamic measurements suggested that p21-GFP was recruited with slower kinetics. An exogenously expressed p21 mutant protein unable to bind PCNA neither colocalised, nor coimmunoprecipitated with PCNA after UV irradiation. In NER-deficient XP-A fibroblasts, p21 relocation was greatly delayed, concomitantly with that of PCNA. These results indicate that early recruitment of p21 protein to DNA-damage sites is a NER-related process dependent on interaction with PCNA, thus suggesting a direct involvement of p21 in DNA repair.

Key words: p21^waf1/cip1, PCNA, DNA repair, Nucleotide excision repair, UV irradiation

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