Functional genomic screens identify CINP as a genome maintenance protein.

Lovejoy CA, Xu X, Bansbach CE, Glick GG, Zhao R, Ye F, Sirbu BM, Titus LC, Shyr Y, Cortez D
Proc Natl Acad Sci U S A. 2009 106 (46): 19304-9

PMID: 19889979 · PMCID: PMC2780779 · DOI:10.1073/pnas.0909345106

The DNA damage response (DDR) has a critical role in maintaining genome integrity and serves as a barrier to tumorigenesis by promoting cell-cycle arrest, DNA repair, and apoptosis. The DDR is activated not only by genotoxic agents that induce DNA damage, but also during aberrant cell-division cycles caused by activated oncogenes and inactivated tumor suppressors. Here we use RNAi and cDNA overexpression screens in human cells to identify genes that, when deregulated, lead to activation of the DDR. The RNAi screen identified 73 genes that, when silenced in at least two cell types, cause DDR activation. Silencing several of these genes also caused an increased frequency of micronuclei, a marker of genetically unstable cells. The cDNA screen identified 97 genes that when overexpressed induce DDR activation in the absence of any exogenous genotoxic agent, with an overrepresentation of genes linked to cancer. Secondary RNAi screens identified CDK2-interacting protein (CINP) as a cell-cycle checkpoint protein. CINP interacts with ATR-interacting protein and regulates ATR-dependent signaling, resistance to replication stress, and G2 checkpoint integrity.

MeSH Terms (13)

Adaptor Proteins, Signal Transducing Ataxia Telangiectasia Mutated Proteins Carrier Proteins Cell Cycle Proteins DNA-Binding Proteins DNA Damage Genome, Human Genomics Genomics HeLa Cells Humans Protein-Serine-Threonine Kinases Two-Hybrid System Techniques

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