The CDK Subunit CKS2 Counteracts CKS1 to Control Cyclin A/CDK2 Activity in Maintaining Replicative Fidelity and Neurodevelopment

Mattia Frontini, Alexander Kukalev, Elisabetta Leo, Yiu-Ming Ng, Marcella Cervantes, Chi-Wai Cheng, Roman Holic, Dirk Dormann, Eric Tse, Yves Pommier, Veronica Yu
2012 Developmental Cell  
CKS proteins are evolutionarily conserved cyclindependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCF SKP2 to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2 À/À knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2 À/À cells leads to loss of p27. The
more » ... sulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2 À/À cortical progenitor cells are limited in their capacity to differentiate into mature neurons, a phenotype akin to animals lacking p27. We propose that the balance between CKS2 and CKS1 modulates p27 degradation, and with it cyclin A/CDK2 activity, to safeguard replicative fidelity and control neuronal differentiation.
doi:10.1016/j.devcel.2012.06.018 pmid:22898779 pmcid:PMC3898080 fatcat:3rdqbq6zzfcxje763alj6yhaee