P21Cip1/waf1 differentially regulates DNA replication and DNA repair-associated processes after UV

SORIA G; SPERONI J; BELLUSCIO L AND GOTTIFREDI V

Ventura, California, USA

Congreso; Gordon Research Conference in DNA Damage, Mutation and Cance€r; 2008

Although p21 up-regulation is required to block cell cycle progression after many types of genotoxic insults, UV irradiation triggers p21 proteolysis. The significance of the increased p21 turnover is unclear and might be associated to DNA repair. While the role of p21 in Nucleotide Excision Repair (NER) remains controversial, recent reports explore its effect on Translesion DNA Synthesis (TLS), a process that avoids replication blockage during S phase. Herein we analyze the effect of p21 on different PCNA-driven processes including DNA replication, NER and TLS. Whereas only the CDK binding domain of p21 is required for cell cycle arrest in unstressed cells; neither the CDK- nor the PCNA-binding domains of p21 are able to block early and late steps of NER. Intriguingly, through its PCNA binding domain, p21 inhibited the recruitment of the TLS-polymerase, polh, to PCNA foci after UV. Moreover, this obstruction correlates with accumulation of gH2AX and increased apoptosis.  Taken together, these data suggest that increased p21 proteolysis after UV irradiation might be relevant for efficient by-pass of lesions by translesion polymerases.