When a CDK Is Really a Transcription Factor

Abstract

It has been assumed that cyclin-dependent kinases (CDKs) perform their various functions as a consequence of their kinase activity, which is regulated by interaction with cyclins. In mediating cell cycle progression, this is clearly true; however, Yu et al. suggest a kinase-independent function for the yeast Cdc28, the homolog of mammalian Cdk1. Using the induction of GAL1 expression in response to a change in carbon source, the authors showed that both cks1 mutants and cdc28 mutants exhibited decreased expression of GAL1. (Cks1 is a protein that interacts with Cdc28 in a manner separate from the cyclin binding site on Cdc28 and that does not appear to regulate the kinase activity of Cdc28.) Using multiple methods, from chemical inhibition of a modified version of Cdc28 to analysis under conditions when the kinase activity should be inhibited due to lack of cyclins or in the presence of kinase-dead mutants of Cdc28, the kinase activity of Cdc28 was dispensable for the stimulation of GAL1 in response to galactose. Using chromatin immunoprecipitation experiments, Cks1 and Cdc28 were found to be present on the promoter of GAL1 and the open reading frame (ORF). Furthermore, in the presence of glucose, which represses GAL1 transcription, Cks1 and Cdc28 were specifically depleted from the ORF and not the upstream regions of the GAL1 gene. Binding of Cks1 or Cdc28 to GAL1 required the presence of and interaction between both proteins. The Cks1 and Cdc28 complex appeared to recruit the proteasome to the ORF, thereby facilitating transcription elongation. In strains lacking functional Cks1 or Cdc28, the recruitment to GAL1 of the proteasomal subunit Rpt1 was reduced. Thus, the CDK Cdc28 appears to play a direct role in transcriptional elongation that is independent of their kinase activities. V. P. C. C. Yu, C. Baskerville, B. Grünenfelder, S. I. Reed, A kinase-independent function of Cks1 and Cdk1 in regulation of transcription. Mol. Cell 17 , 145-151 (2005). [PubMed]