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Vol. 13, Issue 5, 1536-1549, May 2002
§
Departments of *Molecular and Cellular Biology and
The highly conserved Cdc6 protein is required for initiation of
eukaryotic DNA replication and, in yeast and Xenopus,
for the coupling of DNA replication to mitosis. Herein, we show that human Cdc6 is rapidly destroyed by a p53-independent, proteasome-, and
ubiquitin-dependent pathway during early stages of programmed cell
death induced by the DNA-damaging drug adozelesin, or by a separate
caspase-dependent pathway in cells undergoing apoptosis through an
extrinsic pathway induced by tumor necrosis factor-Cancer Genetics, Roswell Park Cancer Institute, Buffalo,
New York 14263; ¶Department of Endocrinology and
Metabolism, City of Hope National Medical Center, Duarte, California
91010; and Centro de Biologia Molecular "Severo
Ochoa", Consejo Superior de Investigaciones Cientificas and
Universidad Autonoma de Madrid, 28049 Madrid, Spain
and
cycloheximide. The proteasome-dependent pathway induced by adozelesin
is conserved in the budding yeast Saccharomyces
cerevisiae. The destruction of Cdc6 may be a primordial
programmed death response that uncouples DNA replication from the cell
division cycle, which is reinforced in metazoans by the evolution of
caspases and p53.
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