Review Multiple roles of the cell cycle inhibitor p21 CDKN1A in the DNA damage response Ornella Cazzalini a , A. Ivana Scovassi b , Monica Savio a , Lucia A. Stivala a , Ennio Prosperi b,c, * a Dipartimento di Medicina Sperimentale, sez. Patologia Generale ‘‘C. Golgi’’, Universita ` di Pavia, 27100 Pavia, Italy b Istituto di Genetica Molecolare del CNR (IGM-CNR), 27100 Pavia, Italy c Dipartimento di Biologia Animale, Universita ` di Pavia, 27100 Pavia, Italy Contents 1. Introduction ...................................................................................................... 12 2. Roles of p21 in DNA damage response ................................................................................. 13 2.1. Cell-cycle regulation .......................................................................................... 13 2.2. Apoptosis................................................................................................... 14 2.3. Transcription regulation ....................................................................................... 15 2.4. DNA repair ................................................................................................. 15 3. Post-translational regulation of p21 in the DNA damage response ........................................................... 16 4. Conclusions and perspectives ........................................................................................ 17 Acknowledgements ................................................................................................ 17 References ....................................................................................................... 17 1. Introduction Exposure to different environmental stress conditions, includ- ing radiation (like ionizing and UV radiation), may induce the formation of a variety of DNA genotoxic lesions that cells must remove in order to avoid genomic instability, and to prevent cancer formation. To this end, virtually every organism has developed highly conserved genome surveillance and signaling mechanisms, collectively known as the DNA damage response (DDR). This pathway consists of DNA damage signaling cascade (cell cycle checkpoints), and of DNA repair processes able to recognize and remove a great number of DNA lesions [1]. Among the factors involved in this pathway, p21 CDKN1A protein contributes to the cell response to DNA damage, by regulating fundamental processes, like cell cycle progression, apoptosis, and Mutation Research 704 (2010) 12–20 ARTICLE INFO Article history: Received 14 September 2009 Received in revised form 29 December 2009 Accepted 13 January 2010 Available online 22 January 2010 Keywords: p21CDKN1A DNA repair Cell cycle checkpoints DNA damage response PCNA interaction ABSTRACT Among cell cycle regulatory proteins that are activated following DNA damage, the cyclin-dependent kinase inhibitor p21 CDKN1A plays essential roles in the DNA damage response, by inducing cell cycle arrest, direct inhibition of DNA replication, as well as by regulating fundamental processes, like apoptosis and transcription. These functions are performed through the ability of p21 to interact with a number of proteins involved in these processes. Despite an initial controversy, during the last years several lines of evidence have also indicated that p21 may be directly involved in DNA repair. In particular, the participation of p21 in nucleotide excision repair (NER), base excision repair (BER), and DNA translesion synthesis (TLS), has been suggested to occur thanks to its interaction with proliferating cell nuclear antigen (PCNA), a crucial protein involved in several aspects of DNA metabolism, and cell-cycle regulation. In this review, the multiple roles of p21 in the DNA damage response, including regulation of cell cycle, apoptosis and gene transcription, are discussed together with the most recent findings supporting the direct participation of p21 protein in DNA repair processes. In particular, spatio-temporal dynamics of p21 recruitment to sites of DNA damage will be considered together with several lines of evidence indicating a regulatory role for p21. In addition, the relevance of post-translational regulation in the fate (e.g. degradation) of p21 protein after cell exposure to DNA damaging agents will be analyzed. Both sets of evidence will be discussed in terms of the overall DNA damage response. ß 2010 Elsevier B.V. All rights reserved. * Corresponding author at: IGM-CNR, sez. Istochimica e Citometria, Via Ferrata 1, 27100 Pavia, Italy. Tel.: +39 0382 986267; fax: +39 0382 986430. E-mail address: prosperi@igm.cnr.it (E. Prosperi). Contents lists available at ScienceDirect Mutation Research/Reviews in Mutation Research journal homepage: www.elsevier.com/locate/reviewsmr Community address: www.elsevier.com/locate/mutres 1383-5742/$ – see front matter ß 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.mrrev.2010.01.009