Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated...

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Cdc6 is a bifunctional AAA+ ATPase crucial for DNA replication initiation.
• Both Cdc6 and Apaf-1 (apoptosome component) are activated by the E2F transcription factor during the G1-S transition.
• This co-activation presents a paradox, as genes for cell proliferation and cell death are regulated by the same factor.

Purpose of the Study:

• To resolve the paradox of E2F co-activating cell proliferation and death genes.
• To investigate the role of Cdc6 beyond its known functions in DNA replication.
• To elucidate the mechanism by which Cdc6 might regulate apoptosis.

Main Methods:

• Studied Cdc6 function in proliferating rodent fibroblasts.
• Investigated the interaction of Cdc6 with Apaf-1 and its effect on apoptosome assembly.
• Assessed the role of Cdc6's ATPase domain and cyclin-binding motif in apoptosome inhibition.

Main Results:

• Cdc6 inhibits apoptosome assembly by forming stable complexes with cytochrome c-activated Apaf-1 monomers.
• This inhibitory function relies on Cdc6's ATPase domain, not its cyclin-binding motif.
• Cdc6 suppresses apoptosis induced by various mechanisms, even in non-cytochrome c-dependent pathways.

Conclusions:

• Cdc6 acts as a crucial regulator preventing unintended apoptosis during cell proliferation.
• Cdc6 possesses a novel, third function: inhibiting the apoptosome.
• This AAA+ ATPase plays a vital role in maintaining cellular life by balancing proliferation and cell death pathways.