The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin
The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin
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DOI：
10.1074/jbc.c000276200
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发表时间：
2000-08-04
影响因子：
4.8
通讯作者：
Bishop, DK
中科院分区：
文献类型：
--
作者：
Bhattacharyya, A;Ear, US;Bishop, DK
乳腺癌肿瘤易感基因BRCA 1和BRCA 2的突变使女性易患早发性乳腺癌和其他恶性肿瘤。Brca基因参与多种细胞过程以响应DNA损伤，包括检查点激活、基因转录和DNA修复。与重组修复蛋白Rad 51的生化相互作用（Scully，R.，陈杰，奥克斯河L.，Keegan，M.，Hoekstra，M.，Feunteun，J.，和利文斯顿，D. M.（1997）Cell 90，425-435），以及遗传证据（Moynahan，M. E、赵，J.W.，叫吧，B。H、Jasin，M.（1999）Mol. Cell 4，511-818和Snouwaert，J.N.，高恩湖C.的方法，Latour，A. M.，Mohn，A. R.，Xiao，A.，DiBiase，L.，和Roller，B。H.（1999）Oncogene 18，7900-7907）证明了Brca 1参与DNA双链断裂的重组修复。使用同基因Brca 1（+/+）和brca 1（-/-）小鼠胚胎干（ES）细胞系，我们研究了Brca 1在对两种不同类型DNA损伤的细胞应答中的作用：X射线诱导的损伤和由化疗剂，顺铂，正常和brca 1（-/-）的免疫荧光研究突变小鼠ES细胞系表明，Brca 1促进组装的亚核Rad 51焦点后，两种类型的DNA损伤。这些病灶可能是Rad 51的寡聚复合物，参与DNA损伤的修复或允许细胞在DNA复制期间耐受此类损伤的过程。克隆形成试验表明，与野生型细胞相比，brca 1（-/-）突变体对顺铂的敏感性高5倍。我们的研究表明，Brca 1通过促进Rad 51的组装而有助于损伤修复和/或耐受。这一功能似乎与Brca 2共享。
Mutations in breast cancer tumor susceptibility genes, BRCA1 and BRCA2, predispose women to early onset breast cancer and other malignancies. The Brca genes are involved in multiple cellular processes in response to DNA damage including checkpoint activation, gene transcription, and DNA repair. Biochemical interaction with the recombinational repair protein Rad51 (Scully, R., Chen, J., Ochs, R. L., Keegan, M., Hoekstra, M., Feunteun, J., and Livingston, D. M. (1997) Cell 90, 425-435), as well as genetic evidence (Moynahan, M. E., Chiu, J.W., holler, B. H., and Jasin, M. (1999) Mol. Cell 4, 511-818 and Snouwaert, J. N., Gowen, L. C., Latour, A. M., Mohn, A. R., Xiao, A., DiBiase, L., and Roller, B. H. (1999) Oncogene 18, 7900-7907), demonstrates that Brca1 is involved in recombinational repair of DNA double strand breaks. Using isogenic Brca1(+/+) and brca1(-/-) mouse embryonic stem (ES) cell lines, we investigated the rob of Brca1 in the cellular response to two different categories of DNA damage: x-ray induced damage and cross-linking damage caused by the chemotherapeutic agent, cisplatinum, Immunoflourescence studies with normal and brca1(-/-) mutant mouse ES cell lines indicate that Brca1 promotes assembly of subnuclear Rad51 foci following both types of DNA damage. These foci are likely to be oligomeric complexes of Rad51 engaged in repair of DNA lesions or in processes that allow cells to tolerate such lesions during DNA replication. Clonogenic assays show that brca1(-/-) mutants are 5-fold more sensitive to cisplatinum compared with wild-type cells. Our studies suggest that Brca1 contributes to damage repair and/or tolerance by promoting assembly of Rad51. This function appears to be shared with Brca2.