Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast.
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-alpha 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.
Blanchard
Frederic
F
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Rusiniak
Michael E
ME
Sharma
Karuna
K
Sun
Xiaolei
X
Todorov
Ivan
I
Castellano
M Mar
MM
Gutierrez
Crisanto
C
Baumann
Heinz
H
Burhans
William C
WC
D017209:Apoptosis / Q000502:physiology*; D001572:Benzofurans; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000528:radiation effects; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D053138:Cyclohexenes; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000502:physiology*; D004271:DNA, Fungal / Q000096:biosynthesis; D000080890:Duocarmycins; D005347:Fibroblasts; D006801:Humans; D007211:Indoles; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D001572:Benzofurans; C066503:CDC6 protein, S cerevisiae; C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D004271:DNA, Fungal; D000080890:Duocarmycins; D007211:Indoles; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C060090:adozelesin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex