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Mol Cell Biol. 2017 Sep 26;37(20). pii: e00344-17. doi: 10.1128/MCB.00344-17. Print 2017 Oct 15.

CKS Proteins Promote Checkpoint Recovery by Stimulating Phosphorylation of Treslin.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
3
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA sreed@scripps.edu.

Abstract

CKS proteins are small (9-kDa) polypeptides that bind to a subset of the cyclin-dependent kinases. The two paralogs expressed in mammals, Cks1 and Cks2, share an overlapping function that is essential for early development. However, both proteins are frequently overexpressed in human malignancy. It has been shown that CKS protein overexpression overrides the replication stress checkpoint, promoting continued origin firing. This finding has led to the proposal that CKS protein-dependent checkpoint override allows premalignant cells to evade oncogene stress barriers, providing a causal link to oncogenesis. Here, we provide mechanistic insight into how overexpression of CKS proteins promotes override of the replication stress checkpoint. We show that CKS proteins greatly enhance the ability of Cdk2 to phosphorylate the key replication initiation protein treslin in vitro Furthermore, stimulation of treslin phosphorylation does not occur by the canonical adapter mechanism demonstrated for other substrates, as cyclin-dependent kinase (CDK) binding-defective mutants are capable of stimulating treslin phosphorylation. This effect is recapitulated in vivo, where silencing of Cks1 and Cks2 decreases treslin phosphorylation, and overexpression of wild-type or CDK binding-defective Cks2 prevents checkpoint-dependent dephosphorylation of treslin. Finally, we provide evidence that the role of CKS protein-dependent checkpoint override involves recovery from checkpoint-mediated arrest of DNA replication.

KEYWORDS:

CKS protein; checkpoint recovery; replication stress checkpoint; treslin; treslin phosphorylation

PMID:
28739856
PMCID:
PMC5615187
DOI:
10.1128/MCB.00344-17
[Indexed for MEDLINE]
Free PMC Article

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