Timely degradation of p21 is required to facilitate damaged-DNA replication and to preserve genomic stability after UV irradiation

S MANSILLA, MB VALLERGA, HABIF M, SPERONI J, MB FEDERICO AND GOTTIFREDI V

Sao Paolo

Conferencia; V Meeting in Fundamental Aspects of DNA Repair and Mutagenesis, V FARM-DNA; 2013

USP conferences

While many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agents such as UV irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant to the cellular response to UV irradiation. Here we show that forced p21 stabilization after UV irradiation causes persistent defects in DNA replication which are associated with lasting deficiencies in the recruitment of DNA polymerases in the Y family (involved in translesion DNA synthesis -TLS) to DNA and with the accumulation of DNA damage markers and genomic instability. Remarkably, such noxious effects disappear when disrupting the PCNA interacting motif (PIP) of stable p21, thus suggesting that release of PCNA from p21 interaction is sufficient to allow the recruitment to PCNA of partners (such as Y polymerases) relevant for the UV response. Degradable p21 only transiently delays early replication events and immediate Y polymerase recruitment to DNA after UV irradiation. These temporary effects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. This suggests that a biologically relevant consequence of UV-triggered p21 degradation is to prevent irreversible replication defects by facilitating the tolerance of UV induced DNA lesions.