細(xì)胞具有復(fù)雜的調(diào)控和修復(fù)DNA損傷的復(fù)雜系統(tǒng),，但研究人員一直不清楚DNA初始的損傷信號(hào)如何實(shí)現(xiàn)修復(fù)應(yīng)答的過(guò)程。
最近索爾克生物研究所的研究人員解決了這個(gè)重要的生物學(xué)難題,，在一篇發(fā)表于12月24日出版的Molecular Cell雜志的研究報(bào)告中,，他們表明，一種命名為CtIP的蛋白質(zhì)在DNA損傷后的“信號(hào)-修復(fù)”的轉(zhuǎn)換過(guò)程中起關(guān)鍵作用,。
由于CtIP蛋白在酵母細(xì)胞中參與DNA損傷末端的修復(fù)過(guò)程,，并且人類DNA發(fā)生損傷時(shí)該蛋白也出現(xiàn)在損傷位點(diǎn),，因此該課題組想了解CtIP蛋白在人類細(xì)胞的功能與酵母細(xì)胞中的功能是否相似,。課題組使人類細(xì)胞CtIP蛋白耗盡并使DNA發(fā)生損傷。研究人員發(fā)現(xiàn),，當(dāng)缺失CtIP蛋白質(zhì),，細(xì)胞中DNA的修復(fù)過(guò)程將被中斷。
為了更好地了解CtIP蛋白如何參與DNA的修復(fù)過(guò)程,，以及CtIP蛋白的哪一個(gè)區(qū)域結(jié)合到DNA的損傷末端,，研究人員對(duì)該蛋白的每個(gè)結(jié)構(gòu)域進(jìn)行測(cè)試，他們發(fā)現(xiàn),，CtIP蛋白的中心區(qū)域可結(jié)合到DNA損傷位點(diǎn),。他們將這部分區(qū)域命名為“damage recruitment(DR)”結(jié)構(gòu)域。
進(jìn)一步研究表明,，DR結(jié)構(gòu)域通常情況下隱藏在CtIP折疊蛋白的內(nèi)部,，只有當(dāng)細(xì)胞將DNA損傷信號(hào)傳遞到CtIP的DR結(jié)構(gòu)域并且DR結(jié)構(gòu)域暴露出來(lái)，CtIP才能與DNA損傷位點(diǎn)結(jié)合,，從而引發(fā)一系列的DNA修復(fù)反應(yīng),。（生物谷Bioon.com）
生物谷推薦原始出處：
Molecular Cell, 24 December 2009 doi:10.1016/j.molcel.2009.12.002
CtIP Links DNA Double-Strand Break Sensing to Resection
Zhongsheng You1, 2, , , Linda Z. Shi4, Quan Zhu3, Peng Wu1, You-Wei Zhang2, 6, Andrew Basilio4, Nina Tonnu3, Inder M. Verma3, Michael W. Berns4, 5 and Tony Hunter2, ,
1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Molecular and Cell Biology Laboratory, The Salk Institute, La Jolla, CA 92037, USA
3 Laboratory of Genetics, The Salk Institute, La Jolla, CA 92037, USA
4 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
5 Beckman Laser Institute and Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92715, USA
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.
