Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells
Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells
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DOI：
10.1016/s1097-2765(00)80466-9
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发表时间：
1999-03-01
期刊：
影响因子：
16
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Xu, XL;Weaver, Z;Deng, CX
Brca1肿瘤抑制基因的种系突变使女性易患乳腺癌和卵巢癌。为了研究Brca1相关肿瘤发生的机制，我们获得了携带Brca1基因外显子11靶向缺失的小鼠胚胎成纤维细胞。我们发现突变细胞维持完整的G(1)-S细胞周期检查点并且增殖不良，然而，这些细胞中有缺陷的G(2)-M检查点伴随着广泛的染色体异常。突变型成纤维细胞含有多个功能性中心体，导致染色体分离不平等、核分裂异常和非整倍体。这些数据揭示了BRCA1通过调控中心体复制和G(2)-M检查点在维持遗传稳定性方面的重要作用，并为BRCA1在肿瘤发生中的作用提供了分子基础。
Germline mutations of the Brca1 tumor suppressor gene predispose women to breast and ovarian cancers, To study mechanisms underlying BRCA1-related tumorigenesis, we derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene. We show that the mutant cells maintain an intact G(1)-S cell cycle checkpoint and proliferate poorly, However, a defective G(2)-M checkpoint in these cells is accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contain multiple, functional centrosomes, which lead to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncover an essential role of BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G(2)-M checkpoint and provide a molecular basis for the role of BRCA1 in tumorigenesis.