The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells.
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.
Stolz
Ailine
A
Philipps University Marburg, Institute for Molecular Biology and Tumour Research (IMT), D-35037 Marburg, Germany.
Ertych
Norman
N
Kienitz
Anne
A
Vogel
Celia
C
Schneider
Verena
V
Fritz
Barbara
B
Jacob
Ralf
R
Dittmar
Gunnar
G
Weichert
Wilko
W
Petersen
Iver
I
Bastians
Holger
H
D019313:BRCA1 Protein / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability; D006801:Humans; D008938:Mitosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D019313:BRCA1 Protein; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases