Inhibition of BRCA1 in breast cell lines causes the centrosome duplication cycle to be disconnected from the cell cycle.
BRCA1-dependent ubiquitination activity regulates centrosome number in several tissue culture cell lines derived from breast cells. In these experiments, we asked how BRCA1 inhibits centrosome amplification. In general, supernumerary centrosomes can accumulate by three mechanisms: (1) failed cytokinesis and the accumulation of centrosomes by duplication in a repeated S-phase of the cell cycle, (2) disruption of the licensing of centrosome doubling such that they duplicate at inappropriate times in the cell cycle, or (3) fragmentation of the centrosomes. In this study, we found that inhibition of BRCA1 caused premature separation of centrioles and reduplication. By blocking cells in early S-phase before centrosome amplification secondary to BRCA1 inhibition could occur and then releasing, we found that inhibition of BRCA1 caused centrosome amplification between late S-phase and G2/M before the cell divided. These results suggest that normal BRCA1 function is critical in these cell lines to prevent centriole separation and centrosome reduplication before mitosis.
Ko
M J
MJ
Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
Murata
K
K
Hwang
D-S
DS
Parvin
J D
JD
D000230:Adenocarcinoma / Q000378:metabolism; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D002502:Centrioles / Q000378:metabolism; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D016195:G2 Phase; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D042361:Mammary Glands, Human / Q000378:metabolism*; D008938:Mitosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D016196:S Phase
D019313:BRCA1 Protein; D034741:RNA, Small Interfering; D006918:Hydroxyurea