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腾讯登录Nat Struct Mol Biol：DNA损伤修复因子的结构
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神经退行性疾病包括运动失调性毛细血管扩张症（AT,ataxia telangiectasia）和运动失调性毛细血管扩张症样疾病（ATLD），基因组DNA的双链断裂会易化肿瘤或神经退行性疾病形成，是由诸如辐射或环境毒素之类的因素引起。因此，有效修复机制是细胞存活和细胞功能所必需的，所谓的MRN复合物就是修复机制的重要组分，其结构已被阐明。
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MRN复合物由核酶Mre11、三磷酸腺苷酶Rad50和蛋白质Nbs1构成，其中Nbs1蛋白负责招募ATM蛋白，ATM蛋白在DNA损伤及损伤部位的早期细胞反应中起重要作用，但还不清楚MRN复合物如何确切地识别双链断裂。为阐明此问题，研究人员对MRN复合物功能缺陷版突变体的结构进行分析，发现数对Mre11分子形成一种由Nbs1蛋白稳定的弹性二聚体，不同的综合征常以某种癌症易感性、辐射或神经退行性病变敏感性为标志，往往与复合物中各亚基的突变与相关，例如：与ATLD相关联的突变存在于Mre11 与 Nbs1连接域内，可能通过减弱彼此的相互作用来抑制ATM激活。
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<img src="http://www.bioon.com/biology/UploadFiles/201206/2012062110391903.gif" alt="" width="113" height="149" border="0" hspace="0" />
<a title="" href="http://dx.doi.org/10.1038/nsmb.2323" target="_blank">doi:10.1038/nsmb.2323</a>
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<br/><strong>Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling</strong><br/>
Christian B Schiller, Katja Lammens, Ilaria Guerini, Britta Coordes, Heidi Feldmann, Florian Schlauderer, Carolin M?ckel, Alexandra Schele, Katja Str?sser, Stephen P Jackson, Karl-Peter Hopfner
The Mre11-Rad50-Nbs1 (MRN) complex tethers, processes and signals DNA double-strand breaks, promoting genomic stability. To understand the functional architecture of MRN, we determined the crystal structures of theSchizosaccharomyces pombe Mre11 dimeric catalytic domain alone and in complex with a fragment of Nbs1. Two Nbs1 subunits stretch around the outside of the nuclease domains of Mre11, with one subunit additionally bridging and locking the Mre11 dimer via a highly conserved asymmetrical binding motif. Our results show that Mre11 forms a flexible dimer and suggest that Nbs1 not only is a checkpoint adaptor but also functionally influencesMre11-Rad50. Clinical mutations in Mre11 are located along the Nbs1-interaction sites and weaken the Mre11-Nbs1 interaction. However, they differentially affect DNA repair and telomere maintenance in Saccharomyces cerevisiae, potentially providing insight into their different human disease pathologies.
<br/>来源：生物谷
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神经退行性疾病包括运动失调性毛细血管扩张症（AT,ataxia telangiectasia）和运动失调性毛细血管扩张症样疾病（ATLD），基因组DNA的双链断裂会易化肿瘤或神经退行性疾病形成，是由诸如辐射或环境毒素之类的因素引起。因此，有效修复机制是细胞存活和细胞功能所必需的，所谓的MRN复合物就是修复机制的重要组分，其结构已被阐明。
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MRN复合物由核酶Mre11、三磷酸腺苷酶Rad50和蛋白质Nbs1构成，其中Nbs1蛋白负责招募ATM蛋白，ATM蛋白在DNA损伤及损伤部位的早期细胞反应中起重要作用，但还不清楚MRN复合物如何确切地识别双链断裂。为阐明此问题，研究人员对MRN复合物功能缺陷版突变体的结构进行分析，发现数对Mre11分子形成一种由Nbs1蛋白稳定的弹性二聚体，不同的综合征常以某种癌症易感性、辐射或神经退行性病变敏感性为标志，往往与复合物中各亚基的突变与相关，例如：与ATLD相关联的突变存在于Mre11 与 Nbs1连接域内，可能通过减弱彼此的相互作用来抑制ATM激活。
<div id="ztload">
<div> </div>
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201206/2012062110391903.gif" alt="" width="113" height="149" border="0" hspace="0" />
<a title="" href="http://dx.doi.org/10.1038/nsmb.2323" target="_blank">doi:10.1038/nsmb.2323</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling</strong><br/>
Christian B Schiller, Katja Lammens, Ilaria Guerini, Britta Coordes, Heidi Feldmann, Florian Schlauderer, Carolin M?ckel, Alexandra Schele, Katja Str?sser, Stephen P Jackson, Karl-Peter Hopfner
The Mre11-Rad50-Nbs1 (MRN) complex tethers, processes and signals DNA double-strand breaks, promoting genomic stability. To understand the functional architecture of MRN, we determined the crystal structures of theSchizosaccharomyces pombe Mre11 dimeric catalytic domain alone and in complex with a fragment of Nbs1. Two Nbs1 subunits stretch around the outside of the nuclease domains of Mre11, with one subunit additionally bridging and locking the Mre11 dimer via a highly conserved asymmetrical binding motif. Our results show that Mre11 forms a flexible dimer and suggest that Nbs1 not only is a checkpoint adaptor but also functionally influencesMre11-Rad50. Clinical mutations in Mre11 are located along the Nbs1-interaction sites and weaken the Mre11-Nbs1 interaction. However, they differentially affect DNA repair and telomere maintenance in Saccharomyces cerevisiae, potentially providing insight into their different human disease pathologies.
<br/>来源：生物谷
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