IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
p21 regulates the replication of damaged DNA and the genomic stability through its PCNA binding domain
Autor/es:
SABRINA F. MANSILLA; GASTÓN SORIA; MARÍA BELÉN VALLERGA; JULIANA SPERONI; MARÍA BELÉN FEDERICO; MARTÍN HABIF; VANESA GOTTIFREDI
Lugar:
Newport, Rhode Island
Reunión:
Congreso; Gordon Research Conference 2012: Mutagenesis: A Delicate Balance: Cellular Mutation Pathways in Genetic Stability and Disease; 2012
Institución organizadora:
Gordon Research Conference Organizing Comitee
Resumen:
Our laboratory is currently working in describing the role of the cyclin kinase inhibitor p21 in the replication of damage DNA. We have found that p21 is degraded when challenged with UV light. After DNA damage the cell has to deal with different types of lesions which alter the replication dynamic. These alterations can be visualized using the DNA combing assay that allows the analysis of single DNA molecules which correspond to ongoing forks. Interestingly we have found that p21 through its PCNA (Proliferating Cell Nuclear Antigen) binding domain negatively regulates the replication of damage DNA. We have also seen that the stable expression of p21 (which lets the cell cycle as it does not bind CDK complexes) impairs the recruitment of specialized polymerases in charge of dealing with these types of lesions (Translesion Synthesis Polymerases). These polymerases are recruited after DNA damage and have to be tightly regulated as they are mutagenic on undamaged template. Taken together the alteration seen in the replication of damage DNA could be attributed to the lack of access of these polymerases to the site of damage. Moreover we saw a sustained increase in the signal and recruitment of gammaH2AX and 53BP1, two well-known DNA damage response (DDR) markers, when stable expressing p21. In line with these we observed an increase in cell death after UV damage when p21 is present and currently we have seen a correlation with the expression of p21 and the formation of micronuclei, an established genomic instability marker. All together our data indicates that while p21 might be necessary for unnecessary TLS polymerase loading, p21 correct and timely degradation could be preventing cell death and genomic instability by avoiding fork stalling.