INVESTIGADORES
MANSILLA Sabrina Florencia
artículos
Título:
Kinase-independent function of checkpoint kinase 1 (Chk1) in the replication of damaged DNA.
Autor/es:
JULIANA SPERONI; MARIA BELEN FEDERICO; SABRINA MANSILLA; GASTON SORIA; VANESA GOTTIFREDI
Revista:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Editorial:
NATL ACAD SCIENCES
Referencias:
Lugar: Washington DC, USA; Año: 2012 vol. 109 p. 7344 - 7349
ISSN:
0027-8424
Resumen:
The checkpoint kinases Chk1 and ATR are broadly known for their role in
the response to the accumulation of damaged DNA. Because
Chk1 activation requires its
phosphorylation by ATR, it is expected that ATR or Chk1 down-regulation
should cause similar
alterations in the signals triggered by
DNA lesions. Intriguingly, we found that Chk1, but not ATR, promotes the
progression
of replication forks after UV irradiation.
Strikingly, this role of Chk1 is independent of its kinase-domain and
of its partnership
with Claspin. Instead, we demonstrate that
the ability of Chk1 to promote replication fork progression on damaged
DNA templates
relies on its recently identified
proliferating cell nuclear antigen-interacting motif, which is required
for its release
from chromatin after DNA damage. Also
supporting the importance of Chk1 release, a histone H2B-Chk1 chimera,
which is permanently
immobilized in chromatin, is unable to
promote the replication of damaged DNA. Moreover, inefficient chromatin
dissociation
of Chk1 impairs the efficient recruitment
of the specialized DNA polymerase η (pol η) to replication-associated
foci after
UV. Given the critical role of pol η
during translesion DNA synthesis (TLS), these findings unveil an
unforeseen facet of
the regulation by Chk1 of DNA replication.
This kinase-independent role of Chk1 is exclusively associated to the
maintenance
of active replication forks after UV
irradiation in a manner in which Chk1 release prompts TLS to avoid
replication stalling.