Loss of the tumour-suppressor genes CHK2 and BRCA1 results in chromosomal instability.
CHK2 (checkpoint kinase 2) and BRCA1 (breast cancer early-onset 1) are tumour-suppressor genes that have been implicated previously in the DNA damage response. Recently, we have identified CHK2 and BRCA1 as genes required for the maintenance of chromosomal stability and have shown that a Chk2-mediated phosphorylation of Brca1 is required for the proper and timely assembly of mitotic spindles. Loss of CHK2, BRCA1 or inhibition of its Chk2-mediated phosphorylation inevitably results in the transient formation of abnormal spindles that facilitate the establishment of faulty microtubule-kinetochore attachments associated with the generation of lagging chromosomes. Importantly, both CHK2 and BRCA1 are lost at very high frequency in aneuploid lung adenocarcinomas that are typically induced in knockout mice exhibiting chromosomal instability. Thus these results suggest novel roles for Chk2 and Brca1 in mitosis that might contribute to their tumour-suppressor functions.
Philipps University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, D-35037 Marburg, Germany.
Ailine
A
Stolz
Norman
N
Ertych
Holger
H
Bastians
D000782:Aneuploidy; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability; D004249:DNA Damage; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism
D019313:BRCA1 Protein; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases