The replication initiation factor Cdc6 is cleaved during apoptosis, and expression of a cleavage product is sufficient to induce apoptosis in otherwise unstressed cells. On page 77, Yim et al. report that the cleavage products can act as dominant-negative inhibitors of replication and amplify pro-death signals.
In addition to the previously identified cleavage product, Yim et al. identified a second Cdc6 fragment produced by caspase-3. Both Cdc6 fragments were sufficient to induce cell death without additional pro-apoptotic signals. Moreover, in cells exposed to apoptosis-inducing factors, ectopic expression of the Cdc6 peptides increased the rate of cell death. In contrast, expression of noncleavable Cdc6 suppressed apoptosis, indicating that fragmentation of the protein plays a causal role in the process even in the presence of known triggers.
Truncated Cdc6 interferes with loading of Mcm2 on the chromatin and thus disrupts assembly of the prereplication complex on...
