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

Shinichiro Niimi1, Shiho Arakawa-Takeuchi, Baasanjav Uranbileg

  • 1Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

The Journal of Biological Chemistry
|April 12, 2012
PubMed

Insights

Cdc6, a cell cycle regulator, prevents apoptosis by inhibiting the apoptosome. This AAA+ ATPase ensures cell proliferation by balancing cell division and programmed cell death.

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.

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