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NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

Claus Storgaard Sørensen, Marina Melixetian, Ditte Kjærsgaard Klein and Kristian Helin

The DNA damage induced G₂/M checkpoint is an important guardian of the genome that prevents cell division when DNA lesions are present. The checkpoint prevents cells from entering mitosis by degrading CDC25A, a key CDK activator. CDC25A proteolysis is controlled by direct phosphorylation events that lead to its recognition by the ubiquitin ligase β-TrCP. Recently we have identified NEK11, a member of NIMA-related kinase family, as the critical kinase triggering CDC25A degradation. NEK11 controls degradation of CDC25A by directly phosphorylating CDC25A on residues whose phosphorylation is required for β-TrCP mediated CDC25A polyubiquitylation and degradation. The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273. Since inhibition of NEK11 activity forces checkpoint-arrested cells into mitosis and cell death, NEK11 is, like CHK1, a strong candidate target for the development of novel anticancer drugs. Here we further support this notion by showing results suggesting that NEK11 expression increases during colon cancer development.

Authors

Claus Storgaard Sørensen Corresponding author: claus.storgaard@bric.ku.dk

University of Copenhagen; Copenhagen, Denmark

Marina Melixetian

European Institute of Oncology; Milan, Italy

Ditte Kjærsgaard Klein

University of Copenhagen; Copenhagen, Denmark

Kristian Helin Corresponding author: kristian.helin@bric.ku.dk

University of Copenhagen; Copenhagen, Denmark