Cdc48/p97 segregase is modulated by cyclin-dependent kinase to determine cyclin fate during G1 progression

EMBO J. 2018 Aug 15;37(16):e98724. doi: 10.15252/embj.201798724. Epub 2018 Jun 27.


Cells sense myriad signals during G1, and a rapid response to prevent cell cycle entry is of crucial importance for proper development and adaptation. Cln3, the most upstream G1 cyclin in budding yeast, is an extremely short-lived protein subject to ubiquitination and proteasomal degradation. On the other hand, nuclear accumulation of Cln3 depends on chaperones that are also important for its degradation. However, how these processes are intertwined to control G1-cyclin fate is not well understood. Here, we show that Cln3 undergoes a challenging ubiquitination step required for both degradation and full activation. Segregase Cdc48/p97 prevents degradation of ubiquitinated Cln3, and concurrently stimulates its ER release and nuclear accumulation to trigger Start. Cdc48/p97 phosphorylation at conserved Cdk-target sites is important for recruitment of specific cofactors and, in both yeast and mammalian cells, to attain proper G1-cyclin levels and activity. Cdk-dependent modulation of Cdc48 would subjugate G1 cyclins to fast and reversible state switching, thus arresting cells promptly in G1 at developmental or environmental checkpoints, but also resuming G1 progression immediately after proliferative signals reappear.

Keywords: Cdc48; Cln3; ER release; Start; cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cyclins / genetics
  • Cyclins / metabolism*
  • G1 Phase / physiology*
  • HEK293 Cells
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Proteolysis*
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Valosin Containing Protein / genetics
  • Valosin Containing Protein / metabolism*


  • CLN3 protein, S cerevisiae
  • CLN3 protein, human
  • CLN3 protein, mouse
  • Cyclins
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Saccharomyces cerevisiae Proteins
  • CDC48 protein, S cerevisiae
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse