Loss of the tumour-suppressor genes CHK2 and BRCA1 results in chromosomal instability

Abstract

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