The ubiquitin E3 ligase activity of BRCA1 and its biological functions.
The ubiquitin E3 ligase activity of BRCA1 and its biological functions.
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DOI：
10.1186/1747-1028-3-1
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发表时间：
2008-01-07
期刊：
影响因子：
2.3
通讯作者：
Ohta T
中科院分区：
文献类型：
--
作者：
Wu W;Koike A;Takeshita T;Ohta T
基底样乳腺癌是一种预后不良且可能具有独特化疗敏感性的新型乳腺癌，是目前乳腺癌领域研究的热点。来自多个来源的证据强烈表明，BRCA1通路的损伤是导致这种表型的原因，这意味着BRCA1不仅在家族性乳腺癌中很重要，而且在散发性癌症中也很重要。BRCA1作为枢纽蛋白，协调多种细胞通路以维持基因组稳定性。BRCA1参与多种细胞超复合体来执行其任务，并且在大多数复合体中，BRCA1作为环异源二聚体与BARD1存在，以提供泛素E3连接酶活性，这是其肿瘤抑制功能所必需的。最近发现，BRCA1无名指基因能够催化多种类型的泛素化，这取决于泛素载体蛋白E2的相互作用。BRCA1可以根据需要在不同底物上催化不同的泛素化。另一方面，在DNA双链断裂中，BRCA1在同源重组修复中发挥主要作用，最近的证据表明，泛素化是通过含有蛋白RAP80的UIM （ubiquitin interaction motif）将BRCA1招募到受损部位的关键步骤。因此，泛素和BRCA1可能通过多种方式相互影响以执行细胞功能。这种与细胞存活相关的机制的阐明现在备受期待，因为它可能是预测基底样乳腺癌化疗敏感性的关键。
The basal-like breast cancer, a new category of breast cancer associated with poor prognosis and possibly unique chemosensitivity, is a current topic in the breast cancer field. Evidence from multiple sources strongly indicate that impairment of BRCA1 pathways is responsible for this phenotype, implying the importance of BRCA1 not only in familial breast cancers but also in sporadic cancers. BRCA1 acts as a hub protein that coordinates a diverse range of cellular pathways to maintain genomic stability. BRCA1 participates in multiple cellular supercomplexes to execute its tasks and, in most of the complexes, BRCA1 exists as a RING heterodimer with BARD1 to provide ubiquitin E3 ligase activity that is required for its tumor suppressor function. It was revealed recently that the BRCA1 RING finger is capable of catalyzing multiple types of ubiquitination depending upon the interacting E2, the ubiquitin carrier protein. BRCA1 may catalyze distinct ubiquitination on different substrates as the situation demands. On the other hand, in response to DNA double-strand breaks where BRCA1 plays its major role for homologous recombination repair, recent evidence showed that ubiquitination is a critical step to recruit BRCA1 to the damaged site through UIM (ubiquitin interacting motif) containing protein RAP80. Thus, ubiquitin and BRCA1 likely affect each other in many ways to perform cellular functions. Elucidation of this mechanism in relation to cell survival is now much anticipated because it could be a key to predict chemosensitivity of basal-like breast cancer.
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