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Abstract
At the Xenopus midblastula transition (MBT), cell cycles lengthen, and checkpoints
that respond to damaged or unreplicated DNA are established. The MBT is triggered
by a critical nucleocytoplasmic (N/C) ratio; however, the molecular basis for its
initiation remains unknown. In egg extracts, activation of Chk1 checkpoint kinase
requires the adaptor protein Claspin, which recruits Chk1 for phosphorylation by ATR.
At the MBT in embryos, Chk1 is transiently activated to lengthen the cell cycle. We
show that Xenopus Claspin is phosphorylated at the MBT at both DNA replication checkpoint-dependent
and -independent sites. Further, in egg extracts, Claspin phosphorylation depends
on a threshold N/C ratio, but occurs even when ATR is inhibited. Not all phosphorylation
that occurs at the MBT is reproduced in egg extracts. Our results identify Claspin
as the most upstream molecule in the signaling pathway that responds to the N/C ratio
and indicate that Claspin may also respond to an independent timer to trigger the
MBT and activation of cell cycle checkpoints.