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

Mattia Frontini, Alexander Kukalev, Elisabetta Leo, [No Value] Yiu-Ming Ng, Marcella Cervantes, Chi-Wai Cheng, Roman Holic, Dirk Dormann, Eric Tse, Yves Pommier, Veronica Yu

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

CKS proteins are evolutionarily conserved cyclin-dependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCFSKP2 to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2(-/-) knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2-/- cells leads to loss of p27. The resulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2(-/-) 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.

Original languageEnglish
Pages (from-to)356-370
Number of pages15
JournalDevelopmental Cell
Volume23
Issue number2
DOIs
Publication statusPublished - 14 Aug 2012

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