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Vol. 13, Issue 10, 3662-3671, October 2002
Division of Signal Transduction, Department of Medicine, Beth
Israel Deaconess Medical Center, Boston, Massachusetts 02215; and
Department of Cell Biology, Harvard Medical School, Boston,
Massachusetts 02115
Geminin is an unstable inhibitor of DNA replication that gets
destroyed at the metaphase/anaphase transition. The biological function
of geminin has been difficult to determine because it is not homologous
to a characterized protein and has pleiotropic effects when
overexpressed. Geminin is thought to prevent a second round of
initiation during S or G2 phase. In some assays, geminin induces
uncommitted embryonic cells to differentiate as neurons. In this study,
geminin was eliminated from developing Xenopus embryos
by using antisense techniques. Geminin-deficient embryos show a novel
and unusual phenotype: they complete the early cleavage divisions
normally but arrest in G2 phase immediately after the midblastula
transition. The arrest requires Chk1, the effector kinase of the DNA
replication/DNA damage checkpoint pathway. The results indicate that
geminin has an essential function and that loss of this function
prevents entry into mitosis by a Chk1-dependent mechanism. Geminin may
be required to maintain the structural integrity of the genome or it
may directly down-regulate Chk1 activity. The data also show that
during the embryonic cell cycles, rereplication is almost entirely
prevented by geminin-independent mechanisms.
Present address: Division of Cardiology, Northwestern
University Medical School, Chicago, IL 60611.
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