BRCA2 phosphorylated by PLK1 moves to the midbody to regulate cytokinesis mediated by nonmuscle myosin IIC.
Cytokinesis is the critical final step in cell division. BRCA2 disruption during cytokinesis is associated with chromosome instability, but mechanistic information is lacking that could be used to prevent cancer cell division. In this study, we report that BRCA2 phosphorylation by the mitotic polo-like kinase (PLK1) governs the localization of BRCA2 to the Flemming body at the central midbody, permitting an interaction with nonmuscle myosin IIC (NM-IIC). Formation of an NM-IIC ring-like structure at the Flemming body shows that the IIC-ring relies on its ATPase activity stimulated by interaction with BRCA2 and associated proteins. Notably, inhibiting this binding inactivated the ATPase activity, causing disassembly of the IIC-ring, defective formation of the midbody, and interruption of cytokinesis. An analysis of cancer-associated mutations in BRCA2 at the PLK1-binding site suggests that they may contribute to cytokinetic defects by altering BRCA2 localization. Our findings suggest that BRCA2-dependent IIC-ring formation is a critical step in proper formation of the midbody, offering an explanation for how chromosome instability may arise in breast cancer.
Authors' Affiliations: Department of Molecular Genetics, Medical Research Institute, Tokyo Medical & Dental University, Bunkyo-Ku; and Department of Genetic Diagnosis, the Cancer Institute of JFCR, Koto-Ku, Tokyo, Japan.
Miho
M
Takaoka
Hiroko
H
Saito
Katsuya
K
Takenaka
Yoshio
Y
Miki
Akira
A
Nakanishi
D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops / Q000235:genetics / Q000378:metabolism*; D048749:Cytokinesis / Q000235:genetics; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008938:Mitosis / Q000235:genetics; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D009218:Myosins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1