生物谷报道：研究人员报告说，一组复合蛋白质与肿瘤抑制基因（也被称为乳腺癌易患基因）BRCA1一起工作来修复DNA。虽然BRCA1的确切功能现在仍然不清楚，但是这些发现给对癌症发展和治疗感兴趣的研究人员提供了该基因的更多线索，BRCA1的突变与乳腺癌、卵巢癌、输卵管癌、前列腺癌、以及结肠癌有关。
Bin Wang和共同作者发表在最新一期《科学》杂志上的研究显示，BRCA1被合作伙伴蛋白质Abraxas和Rap80调动到DNA修复位置来修复DNA受损的细胞。Abraxas蛋白质调解Rap80和BRCA1的相互作用。Rap80被招到有DNA损伤的细胞的一个部位。根据Bijan Sobhian和同事、以及Hongtae Kim和共同作者的报告，Raps80将BRCA1标定到DNA损伤的位置，并且在正确的DNA损伤修复响应中起关键作用。在一项涉及DNA损伤修复系统的调节响应有关蛋白质的大规模研究中，Shuhei Matsuoka和同事发现了900多个涉及700多个蛋白质的位置。这个新数据库揭示了比期待的更大的DNA损伤响应网络，同时显示带有DNA损伤的细胞完全改变了其生理特征。这个数据库是研究癌症和神经退化疾病的研究人员寻找新候选基因的资源。John H. J. Petrini针对四篇相关的论文撰写了一篇研究评述。
原始出处:
Science 25 May 2007:
Vol. 316. no. 5828, pp. 1194 - 1198
DOI: 10.1126/science.1139476
Reports
Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage Response
Bin Wang,1 Shuhei Matsuoka,1 Bryan A. Ballif,2* Dong Zhang,1 Agata Smogorzewska,1,3 Steven P. Gygi,2 Stephen J. Elledge1
The BRCT repeats of the breast and ovarian cancer predisposition protein BRCA1 are essential for tumor suppression. Phosphopeptide affinity proteomic analysis identified a protein, Abraxas, that directly binds the BRCA1 BRCT repeats through a phospho-Ser-X-X-Phe motif. Abraxas binds BRCA1 to the mutual exclusion of BACH1 (BRCA1-associated C-terminal helicase) and CtIP (CtBP-interacting protein), forming a third type of BRCA1 complex. Abraxas recruits the ubiquitin-interacting motif (UIM)–containing protein RAP80 to BRCA1. Both Abraxas and RAP80 were required for DNA damage resistance, G2-M checkpoint control, and DNA repair. RAP80 was required for optimal accumulation of BRCA1 on damaged DNA (foci) in response to ionizing radiation, and the UIM domains alone were capable of foci formation. The RAP80-Abraxas complex may help recruit BRCA1 to DNA damage sites in part through recognition of ubiquitinated proteins.
1 Department of Genetics, Center for Genetics and Genomics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
3 Department of Pathology, Massachusetts General Hospital, Boston, MA 02214, USA.
* Present address: Department of Biology, University of Vermont, Burlington, VT 05405, USA.
Present address: Genomic Instability Group, Oncology Research, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
To whom correspondence should be addressed. E-mail: selledge@genetics.med.harvard.edu
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