2012年10月17日 訊 /生物谷BIOON/ --來自莫非特癌癥中心的研究人員與來自南佛羅里達(dá)大學(xué),、杜克大學(xué),、約翰霍普金斯大學(xué)、巴西國家癌癥研究所以及里約熱內(nèi)盧聯(lián)邦教育、科學(xué)與技術(shù)研究所的同事們一起發(fā)現(xiàn)一種被稱作DNA損傷應(yīng)答(DNA damage response, DDR,，也譯作DNA損傷反應(yīng))的修復(fù)DNA損傷的復(fù)雜系統(tǒng)含有人們之前未知的組分,，包括能夠作為敏化劑而被化療藥物靶向的蛋白。研究人員說,，這些靶標(biāo)中的一些可能已經(jīng)讓人們開發(fā)出不少未曾用于癌癥治療的藥物,。相關(guān)研究結(jié)果于9月18日刊登在Science Signaling期刊上。
論文通信作者,、莫非特癌癥中心癌癥流行病學(xué)項(xiàng)目資深成員Alvaro N.A. Monteiro博士說,，“一種被稱作BRCT的結(jié)構(gòu)域在參與DDR網(wǎng)絡(luò)的蛋白中是經(jīng)常存在的。BRCT結(jié)構(gòu)域是一種在DDR中發(fā)揮著關(guān)鍵性作用的蛋白組件,。我們對BRCT結(jié)構(gòu)域進(jìn)行一項(xiàng)系統(tǒng)性分析,，結(jié)果發(fā)現(xiàn)一個(gè)大的相互作用的蛋白網(wǎng)絡(luò)集中在含有BRCT的蛋白之中。就這樣,，我們發(fā)現(xiàn)新的在DDR中發(fā)揮作用的潛在參與者,。這些新的參與者可能組成用于驗(yàn)證藥物反應(yīng)的生物標(biāo)記物或用于疾病治療的靶標(biāo)。”
這些研究數(shù)據(jù)可能被用來構(gòu)建一種更加綜合性的參與DDR的組分和它們之間相互作用的圖譜,。通過DDR系統(tǒng),，蛋白能夠檢測DNA損傷，促進(jìn)修復(fù)和協(xié)調(diào)細(xì)胞周期,。
因?yàn)镈DR缺陷能夠?qū)е掳┌Y,，所以正確發(fā)揮功能的DDR網(wǎng)絡(luò)被認(rèn)為是對抗腫瘤生長的一道屏障?；煼桨咐眠@個(gè)系統(tǒng)的弱點(diǎn)來殺死癌細(xì)胞,。這些新的發(fā)現(xiàn)通過補(bǔ)充關(guān)于與含有BRCT的蛋白密切相聯(lián)系的特異性蛋白的功能方面的信息來擴(kuò)大我們對DDR的了解。
Monteiro說,，“我們能期待建立BRCT-網(wǎng)絡(luò)結(jié)構(gòu)將有助于鑒定出用于治療的潛在敏化劑和加快開發(fā)出新的治療性策略。”(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.
