BRCA1 regulates gamma-tubulin binding to centrosomes.
Centrosomes are the cellular organelles that nucleate microtubules (MTs) via the activity of gamma-tubulin ring complex(s) (gammaTuRC) bound to the pericentriolar material of the centrosomes. BRCA1, the breast and ovarian cancer specific tumor suppressor, inhibits centrosomal MT nucleation via its ubiquitin ligase activity, and one of the known BRCA1 substrates is the key gammaTuRC component, gamma-tubulin. We analyzed the mechanism by which BRCA1 regulates centrosome function using an in vitro reconstitution assay, which includes separately staged steps. Our results are most consistent with a model by which the BRCA1 ubiquitin ligase modifies both gamma-tubulin plus a second centrosomal protein that controls localization of gammaTuRC to the centrosome. We suggest that this second protein is an adapter protein or protein complex that docks gamma-TuRC to the centrosome. By controlling gamma-TuRC localization, BRCA1 appropriately inhibits centrosome function, and loss of BRCA1 would result in centrosome hyperactivity, supernumerary centrosomes and, possibly, aneuploidy.
Sankaran
Satish
S
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Crone
Donna E
DE
Palazzo
Robert E
RE
Parvin
Jeffrey D
JD
D000782:Aneuploidy; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000502:physiology*; D018385:Centrosome / Q000502:physiology; D019398:Genes, BRCA1; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012617:Sea Urchins; D008941:Spindle Apparatus / Q000187:drug effects / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D054875:Ubiquitination; D014981:Xenopus
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D014404:Tubulin; D043743:Ubiquitin-Protein Ligase Complexes