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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

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Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation

Brian J North1, Eric Verdin

  • 1Gladstone Institute of Virology and Immunology, University of California San Francisco, California 94158, USA.

The Journal of Biological Chemistry
|May 10, 2007
PubMed

Insights

SIRT2 protein activity is regulated by phosphorylation at serine 368, impacting cell division and genomic stability. This modification by cyclin-dependent kinase 1 and dephosphorylation by CDC14 phosphatases influences cellular proliferation and response to mitotic stress.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Sirtuins (NAD(+)-dependent enzymes) regulate critical cellular processes including cell division, apoptosis, DNA repair, and longevity.
  • While sirtuin substrates are increasingly identified, the direct regulatory mechanisms governing sirtuin function remain largely unexplored.

Purpose of the Study:

  • To investigate the post-translational modifications regulating the function of human sirtuin 2 (SIRT2).
  • To identify the kinases and phosphatases involved in SIRT2 regulation and elucidate the functional consequences of these modifications.

Main Methods:

  • In vitro and in vivo phosphorylation assays to identify SIRT2 phosphorylation sites.
  • Site-directed mutagenesis to create serine 368 mutants of SIRT2.
  • Cellular assays to assess the impact of SIRT2 phosphorylation on proliferation and genomic stability under mitotic stress.

Main Results:

  • SIRT2 is phosphorylated on serine 368 by cyclin-dependent kinase 1 (CDK1) and dephosphorylated by CDC14A and CDC14B phosphatases.
  • Overexpression of wild-type SIRT2 delays cellular proliferation, a delay dependent on serine 368 phosphorylation.
  • Mutation of serine 368 to alanine reduces hyperploidy in cells subjected to mitotic stress induced by microtubule poisons.

Conclusions:

  • Serine 368 phosphorylation is a key regulatory mechanism for SIRT2 function.
  • SIRT2 phosphorylation by CDK1 influences cell cycle progression and genomic stability, particularly under stress conditions.

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