The CDK subunit CKS2 counteracts CKS1 to control cyclin A/CDK2 activity in maintaining replicative fidelity and neurodevelopment.
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 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(-/-) 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.
Eukaryotic Chromatin Dynamics Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Mattia
M
Frontini
Alexander
A
Kukalev
Elisabetta
E
Leo
Yiu-Ming
YM
Ng
Marcella
M
Cervantes
Chi-Wai
CW
Cheng
Roman
R
Holic
Dirk
D
Dormann
Eric
E
Tse
Yves
Y
Pommier
Veronica
V
Yu
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D017489:CDC28 Protein Kinase, S cerevisiae / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004249:DNA Damage; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
D018797:Cell Cycle Proteins; D019925:Cyclin A; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; C495893:Cdk2 protein, mouse; C474110:Cks1 protein, mouse; C474109:Cks2 protein, mouse; D051357:Cyclin-Dependent Kinase 2