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 MANSILLA; GASTON SORIA; MARIA BELEN VALLERGA; JULIANA SPERONI; MARIA BELEN FEDERICO; MARTIN HABIF; VANESA GOTTIFREDI
Lugar:
Rhode Island, New Port
Reunión:
Conferencia; Gordon Research Conference: Mutagenesis; 2012
Institución organizadora:
Gordon Research Conference
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 gH2AX 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.