BRCA1 Phosphorylation by Aurora-A in the Regulation of G2 to M Transition

Ouchi, Mutsuko; Fujiuchi, Nobuko; Sasai, Kaori; Katayama, Hiroshi; Minamishima, Yohji A.; Ongusaha, Pat P.; Deng, Chu‐Xia; Sen, Subrata; Lee, Sam W.; Ouchi, Toru

doi:10.1074/jbc.m311780200

Cited by 187 publications

(90 citation statements)

References 53 publications

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“…Interestingly, it was recently shown that Aurora-A physically binds and phosphorylates BRCA1 at S308, and the phosphorylation is correlated with impaired function of BRCA1 in regulating G2/M transition (Ouchi et al, 2004). Altogether, these findings suggest a link between Aurora-A overexpression and impaired BRCA1 function in genetic instability and tumorigenesis.…”

Section: Discussionmentioning

confidence: 94%

“…The phosphorylation of these sites is responsible for the inactivation of p53 transactivation activity and degradation of p53, respectively Liu et al, 2004). It was recently shown that Aurora-A physically binds and phosphorylates BRCA1 at S308 (Ouchi et al, 2004). This phosphorylation is correlated with progression of cells from the G2 phase to the M phase, while BRCA1-S308N, a form that cannot be phosphorylated by Aurora-A, behaves like wild-type BRCA1 in reducing number of cells in the M phase when expressed in BRCA1-deficient mouse embryo fibroblasts (MEFs).…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

et al. 2006

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

et al. 2006

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“…mobility intermediate to those of the hyper-and hypophosphorylated BRCA1 species detectable at other cell cycle stages (lanes 1 and 3). The BRCA1 polypeptides of mitotic cells presumably bear a distinctive pattern of post-translational modifications distinct from those of the hypo-and hyperphosphorylated BRCA1 (48). If the hypophosphorylated forms of BRCA1 are indeed more susceptible to proteasomal degradation, then the absence of these forms in prometaphase may explain why ubiquitination of BRCA1 is reduced at this stage of the cell cycle (Fig.…”

Section: Bard1 Expression Stabilizes Exogenous Brca1 By Specifically mentioning

confidence: 99%

Ubiquitination and Proteasomal Degradation of the BRCA1 Tumor Suppressor Is Regulated during Cell Cycle Progression

Choudhury

Xu²,

Baer

2004

Journal of Biological Chemistry

111

106

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by nocodazole. The proteasome-sensitive ubiquitin conjugates of BRCA1 appear to be distinct from BRCA1 autoubiquitination products and are probably catalyzed by the action of other cellular E3 ligases. Interestingly, co-expression of BARD1 inhibits the formation of these conjugates, suggesting that BARD1 serves to stabilize BRCA1 expression in part by reducing proteasome-sensitive ubiquitination of BRCA1 polypeptides. In summary, these data indicate that the cell cycle-dependent pattern of BRCA1 expression is determined in part by ubiquitin-dependent proteasomal degradation.Germline mutations of the BRCA1 gene are responsible for a substantial proportion of hereditary breast and ovarian cancers (1, 2). In this clinical setting, BRCA1 serves as a tumor suppressor that contributes to tumorigenesis through loss of function. The protein it encodes has been implicated in a number of biological processes, including the cellular response to DNA damage (3, 4). In particular, BRCA1 is required for several checkpoints that control cell cycle progression (5, 6) and inhibit mRNA processing (7, 8) after genotoxic stress, as well as for certain modes of DNA repair such as nucleotide excision repair (9, 10) and homology-directed repair of double-strand DNA breaks (11-13). As a key regulator of the DNA damage response, BRCA1 presumably promotes tumor suppression by preserving genomic stability. However, the molecular mechanisms by which it carries out these functions are not understood and, as a consequence, it is still unclear why inherited mutations of the BRCA1 gene predispose women to breast and ovarian cancer.The BRCA1 polypeptide contains two recognizable amino acid motifs: a RING domain near the N terminus and two tandem copies of the BRCT domain at the C terminus (14). In vivo, BRCA1 exists as a heterodimer with BARD1, a distinct protein that harbors a similar array of RING and BRCT motifs (15). Since the phenotypes of mice null for either Brca1 or Bard1 are essentially indistinguishable, the functions of both proteins are likely to be mediated through the BRCA1/BARD1 heterodimer (16), and indeed BARD1 has already been implicated with BRCA1 in homology-directed repair of chromosomal breaks (17). BRCA1 and BARD1 associate by assembling a stable 4-helix bundle from the ␣ helices that flank their respective RING domains (18), and together they form an enzymatic complex that can catalyze ubiquitin polymerization in vitro (19 -24). This enzymatic activity implies that BRCA1/BARD1 functions as an E3 ligase that promotes ubiquitin modification of specific substrate proteins, and that these are likely to include important effectors of BRCA1-mediated tumor suppression (25,26). Although definitive substrates of BRCA1/BARD1have not yet been identified, autoubiquitination of the BRCA1 subunit is observed during in vitro reactions catalyzed by BRCA1/BARD1 (22). In vitro, BRCA1/BARD1 directs the formation of ubiquitin polymers through an unconventional isopeptide linkage involving lysine residue K6 of ubiquitin (27,28). These K6-link...

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“…Aurora kinases have already been shown to phosphorylate a number of different substrates. Specifically, Aurora A phosphorylates TPX2, LIM protein, CDC25B, p53, BRCA1, ASAP, and others (7)(8)(9)(10)(11)(12)(13), whereas Aurora B phosphorylates histone H3, MCAK, histone H2A, topoisomerase II, INCENP, survivin, and CENP-A (14 -20).…”

mentioning

confidence: 99%

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Perrera

Colombo

Valsasina

et al. 2010

Journal of Biological Chemistry

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Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.

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BRCA1 Phosphorylation by Aurora-A in the Regulation of G2 to M Transition

Cited by 187 publications

References 53 publications

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

Ubiquitination and Proteasomal Degradation of the BRCA1 Tumor Suppressor Is Regulated during Cell Cycle Progression

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

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