INVESTIGADORES
MANSILLA Sabrina Florencia
artículos
Título:
UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability.
Autor/es:
SABRINA MANSILLA; GASTON SORIA; MARIA BELEN VALLERGA; MARTIN HABIF; MARTINEZ LOPEZ WILNER; CAROL PRIVES; VANESA GOTTIFREDI
Revista:
NUCLEIC ACIDS RESEARCH
Editorial:
OXFORD UNIV PRESS
Referencias:
Lugar: Oxford; Año: 2013 p. 1 - 10
ISSN:
0305-1048
Resumen:
Although many genotoxic treatments upregulate the cyclin kinase
inhibitor p21, agents such as UV irradiation trigger p21 degradation.
This suggests that p21 blocks a process relevant for the cellular
response to UV. Here, we show that forced p21 stabilization after UV
strongly impairs damaged-DNA replication, which is associated with
permanent deficiencies in the recruitment of DNA polymerases from the Y
family involved in translesion DNA synthesis), with the accumulation of
DNA damage markers and increased genomic instability. Remarkably, such
noxious effects disappear when disrupting the proliferating cell nuclear
antigen (PCNA) interacting motif of stable p21, thus suggesting that
the release of PCNA from p21 interaction is sufficient to allow the
recruitment to PCNA of partners (such as Y polymerases) relevant for the
UV response. Expression of degradable p21 only transiently delays early
replication events and Y polymerase recruitment after UV irradiation.
These temporary defects disappear in a manner that correlates with p21
degradation with no detectable consequences on later replication events
or genomic stability. Together, our findings suggest that the biological
role of UV-triggered p21 degradation is to prevent replication defects
by facilitating the tolerance of UV-induced DNA lesions.