2012年10月17日 讯 /生物谷BIOON/ --来自莫非特癌症中心的研究人员与来自南佛罗里达大学、杜克大学、约翰霍普金斯大学、巴西国家癌症研究所以及里约热内卢联邦教育、科学与技术研究所的同事们一起发现一种被称作DNA损伤应答(DNA damage response, DDR，也译作DNA损伤反应)的修复DNA损伤的复杂系统含有人们之前未知的组分，包括能够作为敏化剂而被化疗药物靶向的蛋白。研究人员说，这些靶标中的一些可能已经让人们开发出不少未曾用于癌症治疗的药物。相关研究结果于9月18日刊登在Science Signaling期刊上。
论文通信作者、莫非特癌症中心癌症流行病学项目资深成员Alvaro N.A. Monteiro博士说，“一种被称作BRCT的结构域在参与DDR网络的蛋白中是经常存在的。BRCT结构域是一种在DDR中发挥着关键性作用的蛋白组件。我们对BRCT结构域进行一项系统性分析，结果发现一个大的相互作用的蛋白网络集中在含有BRCT的蛋白之中。就这样，我们发现新的在DDR中发挥作用的潜在参与者。这些新的参与者可能组成用于验证药物反应的生物标记物或用于疾病治疗的靶标。”
这些研究数据可能被用来构建一种更加综合性的参与DDR的组分和它们之间相互作用的图谱。通过DDR系统，蛋白能够检测DNA损伤，促进修复和协调细胞周期。
因为DDR缺陷能够导致癌症，所以正确发挥功能的DDR网络被认为是对抗肿瘤生长的一道屏障。化疗方案利用这个系统的弱点来杀死癌细胞。这些新的发现通过补充关于与含有BRCT的蛋白密切相联系的特异性蛋白的功能方面的信息来扩大我们对DDR的了解。
Monteiro说，“我们能期待建立BRCT-网络结构将有助于鉴定出用于治疗的潜在敏化剂和加快开发出新的治疗性策略。”(生物谷Bioon.com)
doi: 10.1126/scisignal.2002255
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Charting the Landscape of Tandem BRCT Domain–Mediated Protein Interactions
Nicholas T. Woods1, Rafael D. Mesquita2*, Michael Sweet1,3, Marcelo A. Carvalho2,4, Xueli Li1, Yun Liu5, Huey Nguyen1, C. Eric Thomas6, Edwin S. Iversen Jr.7, Sylvia Marsillac1, Rachel Karchin5, John Koomen6, and Alvaro N. A. Monteiro
Eukaryotic cells have evolved an intricate system to resolve DNA damage to prevent its transmission to daughter cells. This system, collectively known as the DNA damage response (DDR) network, includes many proteins that detect DNA damage, promote repair, and coordinate progression through the cell cycle. Because defects in this network can lead to cancer, this network constitutes a barrier against tumorigenesis. The modular BRCA1 carboxyl-terminal (BRCT) domain is frequently present in proteins involved in the DDR, can exist either as an individual domain or as tandem domains (tBRCT), and can bind phosphorylated peptides. We performed a systematic analysis of protein-protein interactions involving tBRCT in the DDR by combining literature curation, yeast two-hybrid screens, and tandem affinity purification coupled to mass spectrometry. We identified 23 proteins containing conserved BRCT domains and generated a human protein-protein interaction network for seven proteins with tBRCT. This study also revealed previously unknown components in DNA damage signaling, such as COMMD1 and the target of rapamycin complex mTORC2. Additionally, integration of tBRCT domain interactions with DDR phosphoprotein studies and analysis of kinase-substrate interactions revealed signaling subnetworks that may aid in understanding the involvement of tBRCT in disease and DNA repair.
