Human BRCA1 inhibits growth in yeast: Potential use in diagnostic testing
Human BRCA1 inhibits growth in yeast: Potential use in diagnostic testing
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DOI：
10.1073/pnas.94.11.5820
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发表时间：
1997-05-27
影响因子：
11.1
通讯作者：
Klausner, RD
中科院分区：
文献类型：
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作者：
Humphrey, JS;Salim, A;Klausner, RD
BRCA 1的生殖系失活突变导致乳腺癌和卵巢癌的遗传易感性，BRCA 1的截短突变使癌症易感性，并且可以通过蛋白质截短测试或测序来确定，然而，BRCA 1的癌症易感性错义突变难以通过目前使用的基因测试方法与多态性区分，在这里，我们表明BRCA 1或BRCA 1融合GAL 4激活结构域在酿酒酵母中的表达抑制生长，导致小菌落容易与载体转化的对照区分，生长抑制作用可以定位于编码最近描述的BRCA 1 C-末端结构域的序列，BRCA 1融合蛋白的生长抑制不受中性多态性的引入的影响，但通过移码、无义或位于BRCA 1的C-末端305个氨基酸中的疾病相关错义突变。这些观察结果可以允许在酵母中评估许多BRCA 1序列变化的功能意义。另外，生长抑制与野生型BRCA 1的相关性表明，该测定能够检测进化上保守的BRCA 1 C-在人类和酵母细胞中发现的末端结构域和细胞元件。
Germline-inactivating mutations of BRCA1 result in a hereditary predisposition to breast and ovarian cancer, Truncating mutations of BRCA1 predispose to cancer and can be ascertained by protein truncation testing or sequencing, However, cancer-predisposing missense mutations of BRCA1 are difficult to distinguish from polymorphisms by genetic testing methods currently used, Here we show that expression of BRCA1 or BRCA1 fused to a GAL4 activation domain in Saccharomyces cerevesiae inhibits growth, resulting in small colonies easily distinguishable from vector-transformed controls, The growth inhibitory effect can be localized to sequences encoding the recently described BRCA1 C-terminal domains, Growth suppression by a BRCA1 fusion protein is not influenced by introduction of neutral polymorphisms but is diminished or abolished by frameshift, nonsense, or disease-associated missense mutations located in the C-terminal 305 amino acids of BRCA1, These observations may permit the functional significance of many BRCA1 sequence changes to be assessed in yeast, Additionally, the correlation of growth suppression with wild-type forms of BRCA1 suggests that the assay may be capable of detecting functionally conserved interactions between the evolutionarily conserved BRCA1 C-terminal domains and cellular elements found in both human and yeast cells.