Cell Cycle control of Pol eta localization and function

SORIA G, SPERONI J, BELLUSCIO L, MANSILLA S Y GOTTIFREDI V

Belo Horizonte, Brasil

Congreso; IV Meeting in Fundamental Aspects of DNA Repair and Mutagenesis; 2009

Universidad de Minas Gerais

Cell Cycle control of Pol eta localization and function Gaston Soria, Juliana Speroni, Laura Belluscio, Sabrina Mansilla y Vanesa Gottifredi. Cell Cycle and Genomic Stability Laboratory. Fundaci¨®n Instituto Leloir. CONICET.UBA. Buenos Aires. Argentina. E-mail:vgottifredi@leloir.org.ar When DNA is damaged in cells progressing through S phase, replication blockage can be avoided by TLS (Translesion DNA synthesis). This is a replication auxiliary mechanism that relies on the function of specialized polymerases that accomplish DNA damage bypass. The contribution of error-prone DNA polymerases to the DNA damage response has been a subject of great interest in the last decade. Under certain circumstances, TLS polymerases can achieve bypass with good efficiency and fidelity. However, they can also in some cases be mutagenic, and so negative regulators of TLS polymerases would have the important function of inhibiting their recruitment to undamaged DNA templates. Recently work from our group has provided evidence regarding the role of the cyclin kinase inhibitor p21 as a negative regulator of TLS. Interestingly, both the cyclin dependent kinase (CDK) and proliferating cell nuclear antigen (PCNA) binding domains of p21 are involved in different aspects of the modulation of TLS, affecting both the interaction between PCNA and the TLS-specific pol ¦Ç as well as PCNA ubiquitination status. We propose that, in absence of DNA damage p21 may work to impede accidental loading of pol h to undamaged DNA and avoid consequential mutagenesis. After UV irradiation, when TLS plays a decisive role, p21 is progressively degraded. This might allow gradual release of replication fork blockage by TLS polymerases. For these reason, in higher eukaryotes p21 might represent a key regulator of the equilibrium between mutagenesis and cell survival.