Novel function of p21Cip1/waf1 as a modulator of Translesion DNA Synthesis (TLS)

SORIA G, SPERONI J, BELLUSCIO L, PODHAJCER OL, AND GOTTIFREDI V

Carlos Paz, Cordoba, Argentina

Conferencia; XLIV Reunion Annual SAIB; 2008

SAIB

p21 upregulation is required to block cell-cycle progression after many types of genotoxic insult. In contrast, UVirradiation triggers p21 proteolysis. The biological significance of thisincrease in p21 turnover is unclear and might be linked to DNA repair-related procceses. While the role of p21 in nucleotide excision repair (NER) remains controversial, recent reports have explored itseffect on translesion DNA synthesis (TLS), a process that avoidsreplication blockage during S phase. Interestingly, we have recently showed that efficient PCNa ubiquitination, a modification of PCNA relevant for TLS, requires p21 degradation. Moreover, p21 was shown to negatively modulate excessive TLS, thus avoiding mutagenesis. In this work we utilize different single cell analysis approaches to study the effect of p21 on TLS.  We found that trough its its PCNA-binding domain, p21 inhibits the interaction of the TLS polymerase, pol ç (pol eta), with PCNA and impairs the assembly of pol ç foci after UV. Moreover, this obstruction correlates with accumulation of phosphorylated H2AX and increased apoptosis. By showing that p21 is a negative regulator of PCNA-pol ç interaction, our data unveil a link between efficient TLS and UV-induced degradation of p21.