Human replication protein Cdc6 is selectively cleaved by caspase 3 during apoptosis.
In eukaryotes, the initiation of DNA replication involves the ordered assembly on chromatin of pre-replicative complexes (pre-RCs), including the origin recognition complex (ORC), Cdc6, Cdt1 and the minichromosome maintenance proteins (MCMs). In light of its indispensable role in the formation of pre-RCs, Cdc6 binding to chromatin represents a key step in the regulation of DNA replication and cell proliferation. Here, we study the human Cdc6 (HuCdc6) protein during programmed cell death (apoptosis). We find that HuCdc6, but not HuOrc2 (a member of the ORC) or HuMcm5 (one of the MCMs), is specifically cleaved in several human cell lines induced to undergo apoptosis by a variety of stimuli. Expression of caspase-uncleavable mutant HuCdc6 attenuates apoptosis, delaying cell death. Therefore, an important function for cleavage of HuCdc6 is to prevent a wounded cell from replicating and to facilitate death.
Pelizon
Cristina
C
MCR Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK. cpelizon@yahoo.co.uk
d'Adda di Fagagna
Fabrizio
F
Farrace
Lorena
L
Laskey
Ronald A
RA
D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D053938:DNA Fragmentation; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors
C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D009687:Nuclear Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases