Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2.
Germ-line mutations inactivating BRCA2 predispose to cancer. BRCA2-deficient cells exhibit alterations in chromosome number (aneuploidy), as well as structurally aberrant chromosomes. Here, we show that BRCA2 deficiency impairs the completion of cell division by cytokinesis. BRCA2 inactivation in murine embryo fibroblasts (MEFs) and HeLa cells by targeted gene disruption or RNA interference delays and prevents cell cleavage. Impeded cell separation is accompanied by abnormalities in myosin II organization during the late stages in cytokinesis. BRCA2 may have a role in regulating these events, as it localizes to the cytokinetic midbody. Our findings thus link cytokinetic abnormalities to a hereditary cancer syndrome characterized by chromosomal instability and may help to explain why BRCA2-deficient tumors are frequently aneuploid.
Daniels
Matthew J
MJ
University of Cambridge, Cancer Research UK, Department of Oncology and the Medical Research Council (MRC) Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, UK.
Wang
Yunmei
Y
Lee
Miyoung
M
Venkitaraman
Ashok R
AR
D000705:Anaphase; D000782:Aneuploidy; D000818:Animals; D024682:BRCA2 Protein / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018390:Gene Targeting; D024522:Genes, BRCA2; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis; D024462:Myosin Type II / Q000378:metabolism; D034741:RNA, Small Interfering
D024682:BRCA2 Protein; D034741:RNA, Small Interfering; D024462:Myosin Type II