Deubiquitination of γ-tubulin by BAP1 prevents chromosome instability in breast cancer cells.

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Deubiquitination of γ-tubulin by BAP1 prevents chromosome instability in breast cancer cells. / Zarrizi, Reihaneh; Menard, Julien; Belting, Mattias; Massoumi, Ramin.

I: Cancer Research, Vol. 74, Nr. 22, 2014, s. 6499-6508.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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T1 - Deubiquitination of γ-tubulin by BAP1 prevents chromosome instability in breast cancer cells.

AU - Zarrizi, Reihaneh

AU - Menard, Julien

AU - Belting, Mattias

AU - Massoumi, Ramin

PY - 2014

Y1 - 2014

N2 - Microtubule nucleation requires the γ-tubulin ring complex, and during the M phase (mitosis) this complex accumulates at the centrosome to support mitotic spindle formation. The post-translational modification of γ-tubulin through ubiquitination is vital for regulating microtubule nucleation and centrosome duplication. Blocking the BRCA1/BARD1-dependent ubiquitination of γ-tubulin causes centrosome amplification. In the present study, we identified BRCA1 associated protein-1 (BAP1) as a deubiquitination enzyme for γ-tubulin. BAP1 was downregulated in metastatic adenocarcinoma breast cell lines compared to non-cancerous human breast epithelial cells. Furthermore, low expression of BAP1 was associated with reduced overall survival of breast cancer patients. Reduced expression of BAP1 in breast cancer cell lines was associated with mitotic abnormalities. Importantly, rescue experiments including expression of full length but not the catalytic mutant of BAP1 reduced ubiquitination of γ-tubulin and prevented mitotic defects. Our study uncovers a new mechanism for BAP1 involved in deubiquitination of γ-tubulin, which is required to prevent abnormal mitotic spindle formation and genome instability.

AB - Microtubule nucleation requires the γ-tubulin ring complex, and during the M phase (mitosis) this complex accumulates at the centrosome to support mitotic spindle formation. The post-translational modification of γ-tubulin through ubiquitination is vital for regulating microtubule nucleation and centrosome duplication. Blocking the BRCA1/BARD1-dependent ubiquitination of γ-tubulin causes centrosome amplification. In the present study, we identified BRCA1 associated protein-1 (BAP1) as a deubiquitination enzyme for γ-tubulin. BAP1 was downregulated in metastatic adenocarcinoma breast cell lines compared to non-cancerous human breast epithelial cells. Furthermore, low expression of BAP1 was associated with reduced overall survival of breast cancer patients. Reduced expression of BAP1 in breast cancer cell lines was associated with mitotic abnormalities. Importantly, rescue experiments including expression of full length but not the catalytic mutant of BAP1 reduced ubiquitination of γ-tubulin and prevented mitotic defects. Our study uncovers a new mechanism for BAP1 involved in deubiquitination of γ-tubulin, which is required to prevent abnormal mitotic spindle formation and genome instability.

U2 - 10.1158/0008-5472.CAN-14-0221

DO - 10.1158/0008-5472.CAN-14-0221

M3 - Article

VL - 74

SP - 6499

EP - 6508

JO - Cancer research. Supplement

T2 - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 22

ER -