The role of p21 in the replication of damaged DNA

SABRINA MANSILLA; GASTÓN SORIA; JULIANA SPERONI; BELEN FEDERICO; VANESA GOTTIFREDI

Viña del mar

Congreso; XIV Congreso de la Sociedad Latinoamericana de Genética, VIII Congreso de la asociación latinoamericana de mutagénesis, carcinogénesis y teratogénesis ambiental (ALAMCTA); 2010

Sociedad Latinoamericana de Genética

While many genotoxic signals provoke a p53-dependent p21 upregulation, UV irradiation does not strongly induce p21. Moreover, increasing evidences support the activation of p21 degradation signals after UV exposure. To determine the biological impact of p21 downregulation in this scenario we generated non-degradable p21 mutants and explored their impact on TLS (translesion DNA synthesis). This process maintains DNA replication processivity across damaged DNA and involves the functions of specialized polymerases in the Y family. The interaction between p21 and PCNA impairs the UV induced focal organization of specialized polymerases. We also observed a clear reduction in the rates of DNA synthesis after UV irradiation when p21 was present. Taken together, our data indicates that p21 association with stalled replication forks at DNA lesions might interfere with the TLS events across those lesions. Moreover, this might trigger the excessive cell death of UV irradiated cells expressing stable p21 that we have reported in the past. We propose that basal p21 levels at replication forks might block unnecessary recruitment of Y polymerases to DNA during unstressed replication. In turn, when TLS events are required after UV exposure, p21 degradation could promote gradual recruitment of TLS polymerases to DNA to prevent the irreversible stalling of replication forks.