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Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression.

Although the PR-Set7/Set8/KMT5a histone H4 Lys 20 monomethyltransferase (H4K20me1) plays an essential role in mammalian cell cycle progression, especially during G2/M, it remained unknown how PR-Set7 itself was regulated. In this study, we discovered the mechanisms that govern the dynamic regulation of PR-Set7 during mitosis, and that perturbation of these pathways results in defective mitotic progression. First, we found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. This event is important for proper mitotic progression, as constitutive phosphorylation of PR-Set7 resulted in a substantial delay between metaphase and anaphase. Collectively, we elucidated the molecular mechanisms that control PR-Set7 protein levels during mitosis, and demonstrated that its orchestrated regulation is important for normal mitotic progression.

Pubmed ID: 20966048


  • Wu S
  • Wang W
  • Kong X
  • Congdon LM
  • Yokomori K
  • Kirschner MW
  • Rice JC


Genes & development

Publication Data

November 15, 2010

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR058548
  • Agency: NIGMS NIH HHS, Id: GM039023
  • Agency: NIGMS NIH HHS, Id: GM075094
  • Agency: NIGMS NIH HHS, Id: R01 GM039023
  • Agency: NIGMS NIH HHS, Id: R01 GM075094

Mesh Terms

  • Amino Acid Sequence
  • CDC2 Protein Kinase
  • Cells
  • Chromosomes
  • Gene Expression Regulation, Enzymologic
  • HEK293 Cells
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Mitosis
  • Molecular Sequence Data
  • Phosphoric Monoester Hydrolases
  • Phosphorylation
  • Sequence Alignment
  • Ubiquitination