RRC ID 68934
Author Takaoka M, Saito H, Takenaka K, Miki Y, Nakanishi A.
Title BRCA2 phosphorylated by PLK1 moves to the midbody to regulate cytokinesis mediated by nonmuscle myosin IIC.
Journal Cancer Res
Abstract 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.
Volume 74(5)
Pages 1518-28
Published 2014-3-1
DOI 10.1158/0008-5472.CAN-13-0504
PII 0008-5472.CAN-13-0504
PMID 24448238
MeSH Animals BRCA2 Protein / genetics BRCA2 Protein / metabolism* COS Cells Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Chlorocebus aethiops / genetics Chlorocebus aethiops / metabolism* Cytokinesis / genetics Gene Silencing HeLa Cells Humans MCF-7 Cells Mitosis / genetics Myosins / genetics Myosins / metabolism Phosphorylation / genetics Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Spindle Apparatus / genetics Spindle Apparatus / metabolism*
IF 9.727
Human and Animal Cells HeLaS3 COS-7(RCB0539)