Nat Struct Mol Biol:DNA損傷修復因子的結構

神經退行性疾病包括運動失調性毛細血管擴張症（AT,ataxia telangiectasia）和運動失調性毛細血管擴張症樣疾病（ATLD），基因組DNA的雙鏈斷裂會易化腫瘤或神經退行性疾病形成，是由諸如輻射或環境毒素之類的因素引起。因此，有效修復機制是細胞存活和細胞功能所必需的，所謂的MRN複合物就是修復機制的重要組分，其結構已被闡明。

MRN複合物由核酶Mre11、三磷酸腺苷酶Rad50和蛋白質Nbs1構成，其中Nbs1蛋白負責招募ATM蛋白，ATM蛋白在DNA損傷及損傷部位的早期細胞反應中起重要作用，但還不清楚MRN複合物如何確切地識別雙鏈斷裂。為闡明此問題，研究人員對MRN複合物功能缺陷版突變體的結構進行分析，發現數對Mre11分子形成一種由Nbs1蛋白穩定的彈性二聚體，不同的症候群常以某種癌症易感性、輻射或神經退行性病變敏感性為標誌，往往與複合物中各亞基的突變與相關，例如：與ATLD相關聯的突變存在於Mre11 與 Nbs1連接域內，可能通過減弱彼此的相互作用來抑制ATM激活。（生物谷bioon.com）

 

Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling

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.