Cyclin D1
Probably all tumors harbor a certain
degree of genomic instability, underling the tight
connection between DNA damage responses (repair and
checkpoint) and tumorigenesis. In the past, we have
shown that the DNA-damage response to ionizing
radiation is composed of two processes: initiation
and maintenance. DNA damage causes a fast G1-arrest
by rapidly degrading cyclin-D1. Later, this initial
G1-response to DNA damage is maintained and further
strengthened by the stabilization of p53, leading to
the induction of p21cip1.
Cdc6
Activation of the tumor suppressor p53
in response to genotoxic stress imposes cellular
growth arrest or apoptosis. We identified Cdc6, a
licensing factor of the pre-replication complex
(pre-RC), as a novel target of the p53 pathway. We
show that activation of p53 by DNA damage results in
enhanced Cdc6 destruction by the anaphase-promoting
complex (APC). This destruction is triggered by
inhibition of CDK2 mediated CDC6 phosphorylation at
serine 54. Conversely, suppression of p53 expression
results in stabilization of Cdc6. We show that loss
of p53 results in more replicating cells, an effect
that can be reverted by reducing Cdc6 protein
levels. Our data suggest that initiation of DNA
replication is regulated by p53 through Cdc6 protein
stability.
