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The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells

Item Type:Article
Title:The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells
Creators Name:Stolz, A. and Ertych, N. and Kienitz, A. and Vogel, C. and Schneider, V. and Fritz, B. and Jacob, R. and Dittmar, G. and Weichert, W. and Petersen, I. and Bastians, H.
Abstract:Chromosomal instability (CIN) is a major hallmark of human cancer and might contribute to tumorigenesis. 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 pathway. 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.
Keywords:BRCA1 Protein, Cell Line, Chromosomal Instability, Mitosis, Mitotic Spindle Apparatus, Phosphorylation, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Suppressor Proteins
Source:Nature Cell Biology
ISSN:1465-7392
Publisher:Nature Publishing Group (U.K.)
Volume:12
Number:5
Page Range:492-499
Date:May 2010
Official Publication:https://doi.org/10.1038/ncb2051
PubMed:View item in PubMed

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