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首页> 外文期刊>Biochemistry >Solution structure of polymerase mu's BRCT domain reveals an element essential for its role in nonhomologous end joining
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Solution structure of polymerase mu's BRCT domain reveals an element essential for its role in nonhomologous end joining

机译：聚合酶mu的BRCT结构域的溶液结构揭示了其在非同源末端连接中所必需的元件

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摘要

The solution structure and dynamics of the BRCT domain from human DNA polymerase mu, implicated in repair of chromosome breaks by nonhomologous end joining (NHEJ), has been determined using NMR methods. BRCT domains are typically involved in protein-protein interactions between factors required for the cellular response to DNA damage. The pol mu BRCT domain is atypical in that, unlike other reported BRCT structures, the pol mu BRCT is neither part of a tandem grouping, nor does it appear to form stable homodimers. Although the sequence of the pol It BRCT domain has some unique characteristics, particularly the presence of > 10% proline residues, it forms the characteristic alpha beta alpha sandwich, in which three alpha helices are arrayed around a central four-stranded beta-sheet. The structure of helix 0 is characterized by two solvent-exposed hydrophobic residues, F46 and L50, suggesting,that this element may play a role in mediating interactions of pol mu with other proteins. Consistent with this argument, mutation of these residues, as well as the proximal, conserved residue R43, specifically blocked the ability of pol mu to efficiently work together with NHEJ factors Ku and XRCC4-ligase IV to join noncomplementary ends together in vitro. The structural, dynamic, and biochemical evidence reported here identifies a functional surface in the pol mu BRCT domain critical for promoting assembly and activity of the NHEJ machinery. Further, the similarity between the interaction regions of the BRCT domains of pol It and TdT support the conclusion that they participate in NHEJ as alternate polymerases.
机译：已使用NMR方法确定了来自人类DNA聚合酶mu的BRCT域的溶液结构和动力学，涉及通过非同源末端连接（NHEJ）修复染色体断裂。 BRCT结构域通常参与细胞对DNA损伤的反应所需的因子之间的蛋白质-蛋白质相互作用。 pol mu BRCT结构域是非典型的，与其他已报道的BRCT结构不同，pol mu BRCT既不是串联组的一部分，也不似乎形成稳定的同型二聚体。尽管pol It BRCT结构域的序列具有一些独特的特征，特别是存在> 10％的脯氨酸残基，但它形成了特征性的α-β-α三明治，其中三个α螺旋排列在中央四链β-折叠周围。螺旋0的结构以两个暴露于溶剂的疏水残基F46和L50为特征，表明该元素可能在介导pol mu与其他蛋白质的相互作用中起作用。与该论点一致，这些残基以及近端保守残基R43的突变特异性阻断了pol mu与NHEJ因子Ku和XRCC4-ligase IV共同有效地在体外将非互补末端连接在一起的能力。此处报道的结构，动态和生化证据表明，pol mu BRCT域中的功能性表面对于促进NHEJ机械的组装和活性至关重要。此外，pol It和TdT的BRCT结构域的相互作用区域之间的相似性支持了以下结论：它们以交替聚合酶的形式参与NHEJ。

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