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

SABRINA F. MANSILLA; MARÍA BELÉN VALLERGA; MARTÍN HABIF; JULIANA SPERONI; MARÍA BELÉN FEDERICO; VANESA GOTTIFREDI

Sao Pablo

Congreso; "V FARM-DNA" - V Fundamental Aspects of DNA Repair and Mutagenesis. October 31th to November 2nd 2013; 2013

University of Sao Pablo

While many genotoxic treatments upregulate the cyclin kinase inhibitor p21, agent such as UVC irradiation trigger p21 degradation. This suggests that p21 blocks a process relevant for the cellular response to UV. Here we show that forced p21 stabilization after UV, strongly impairs damaged DNA replication, which is associated with permanent deficiencies in the recruitment of DNA polymerases from the Y family (involved in translesion DNA synthesis-TLS) with the accumulation of DNA damage markers and increased genomic instability. Remarkably, such noxious effects disappear when disrupting the PCNA interacting motif (PIP) of stable p21, thus suggesting that the 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. Expression of degradable p21 only transiently delays early replication events and Y polymerase recruitment after UV irradiation. These temporary defects disappear in a manner that correlates with p21 degradation with no detectable consequences on later replication events or genomic stability. Together, our findings suggest that the biological role of UV-triggered p21 degradation is to prevent replication defects by facilitating the tolerance of UV-induced DNA lesions.