SCFßTrcp-mediated
degradation of Claspin regulates recovery from the DNA replication
checkpoint response.
A. Peschiaroli, N. V. Dorrello, D. Guardavaccaro, M. Venere, T.
Halazonetis, N. Sherman and M. Pagano.
Mol Cell, 23: 319-329, 2006
During replicative stress, Claspin mediates the phosphorylation
and consequent activation of Chk1 by ATR. We found that during
recovery from the DNA replication checkpoint response, Claspin
is degraded in a ßTrcp-dependent manner. In vivo, Claspin is
phosphorylated in a canonical DSGxxS degron sequence, which is
typical of ßTrcp substrates. Phosphorylation of Claspin is
mediated by Plk1 and is essential for binding to ßTrcp. In vitro
ubiquitylation of Claspin requires ßTrcp, Plk1 and an intact
DSGxxS degron. Importantly, expression of a stable Claspin
mutant unable to bind ßTrcp prolongs the activation of Chk1,
thereby attenuating the recovery from the DNA replication stress
response and significantly delaying entry into mitosis. Thus,
the SCFßTrcp-dependent degradation of Claspin is necessary for
the efficient and timely termination of the DNA replication
checkpoint. Importantly, in response to DNA damage in G2,
Claspin proteolysis is inhibited to allow the prompt
reestablishment of the checkpoint.
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