Involvement of the cell cycle inhibitor p21CDKN1A in DNA repair

A variety of chemical and physical agents may induce the formation of different lesions in the DNA molecule. These types of DNA damage may be genotoxic to the cells, and must be removed 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. 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. Recent findings have shown that cell cycle checkpoints and DNA repair systems are strictly connected each other. However, the role and the molecular mechanisms underlying these connections are not yet completely understood. Among cell cycle regulatory proteins that are activated following DNA damage, the cyclin-dependent kinase inhibitor p21CDKN1A plays fundamental roles in the DNA damage response by inducing cell cycle arrest, direct inhibition of DNA synthesis, as well as by regulating transcription and apoptosis. During the last years, several lines of evidence have also indicated that p21 may be directly involved in DNA repair. Participation of p21 in DNA repair pathways, like nucleotide excision repair (NER), and base excision repair (BER), is thought to occur thanks to its interaction with Proliferating Cell Nuclear Antigen (PCNA), a crucial protein involved both in DNA replication and repair. In addition, a direct involvement of p21 in DNA trans-lesion synthesis, has been postulated to keep within low levels the mutagenesis intrinsic in this process. In this review, all relevant findings supporting the participation of p21 protein in NER and BER will be presented. In particular, the ability of p21 to interact with PCNA seems to be required for regulating interaction of DNA repair factors with PCNA. Examples of this role will be discussed together with other aspects of the DNA damage response in which p21 is also involved. A special attention will be given to the dynamics of p21 recruitment to sites of DNA damage. In fact, a common feature of checkpoint and DNA repair factors is their accumulation at nuclear sites where DNA damage has occurred. The involvement of p21 in various DNA repair pathways supports its important function of protein barrier against genome instability.