Author: ["Ailine Stolz","Norman Ertych","Anne Kienitz","Celia Vogel","Verena Schneider","Barbara Fritz","Ralf Jacob","Gunnar Dittmar","Wilko Weichert","Iver Petersen","Holger Bastians"]
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Abstract
The DNA-damage checkpoint kinase Chk2 is a candidate tumour suppressor. Independently of DNA damage, Chk2 regulates spindle assembly and maintenance of chromosomal stability through phosphorylation of BRCA1. Chromosomal instability (CIN) is a major hallmark of human cancer and might contribute to tumorigenesis1. Genes required for the normal progression of mitosis represent potential CIN genes and, as such, are important tumour suppressors. The Chk2 kinase and its downstream targets p53 and Brca1 are tumour suppressors that have been functionally linked to the DNA damage response pathway2. Here, we report a function of Chk2, independent of p53 and DNA damage, that is required for proper progression of mitosis, and for the maintenance of chromosomal stability in human somatic cells. Depletion of Chk2 or abrogation of its kinase activity causes abnormal mitotic spindle assembly associated with a delay in mitosis, which promotes the generation of lagging chromosomes, chromosome missegregation and CIN, while still allowing survival and growth. Furthermore, we have identified Brca1 as a mitotic target of the Chk2 kinase in the absence of DNA damage. Accordingly, loss of BRCA1 or its Chk2-mediated phosphorylation leads to spindle formation defects and CIN. Thus, the CHK2–BRCA1 tumour suppressor pathway is required for chromosomal stability, which might contribute to their tumour suppressor function.Cite this article
Stolz, A., Ertych, N., Kienitz, A. et al. The CHK2–BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol 12, 492–499 (2010). https://doi.org/10.1038/ncb2051 