小柯机器人

范可尼贫血ID复合物单泛素化的功能
2020-03-16 14:20

美国纪念斯隆-凯特琳癌症中心Nikola P. Pavletich研究组取得一项新突破。他们揭示了单泛素化范可尼贫血ID复合物的DNA滑钳功能。这一研究成果在线发表于3月11日的《自然》。

研究人员解析了单泛素化人ID复合物与DNA结合的冷冻电镜结构,并发现它形成了一个环绕DNA的闭环。通过对与链间交联键(ICL)DNA结合的非泛素化ID复合物结构(该研究也揭示了其结构)的比较,研究人员发现单泛素化的前体通过交互的方式与另一个前体结合从而完成了开放、槽状ID结构的完全重排。

这些结构连同生化数据协同证明,单泛素化ID复合物失去了对ICL和相关分支DNA结构的偏好,而变成可协调后续修复反应的滑动DNA钳。这项研究还揭示了单泛素化如何能诱导具有新功能的替代蛋白质结构。

据介绍,包含FANCI和FANCD2蛋白的ID复合物是修复DNA链间交联键和相关病变所需的。这些蛋白在范可尼贫血中发生突变,范可尼贫血患者易患癌症。当复制叉停在ICL2上时,会激活ICL修复的范可尼贫血途径。这引起ID复合物的单泛素化,即一个泛素分子分别与FANCI和FANCD2结合。

ID的单泛素化对于通过切除、跨病变合成和同源重组途径进行的ICL修复至关重要。但是,其功能仍然未知。

附:英文原文

Title: DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex

Author: Renjing Wang, Shengliu Wang, Ankita Dhar, Christopher Peralta, Nikola P. Pavletich

Issue&Volume: 2020-03-11

Abstract: The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions. These proteins are mutated in Fanconi anaemia, a disease in which patients are predisposed to cancer. The Fanconi anaemia pathway of ICL repair is activated when a replication fork stalls at an ICL; this triggers monoubiquitination of the ID complex, in which one ubiquitin molecule is conjugated to each of FANCI and FANCD2. Monoubiquitination of ID is essential for ICL repair by excision, translesion synthesis and homologous recombination; however, its function remains unknown. Here we report a cryo-electron microscopy structure of the monoubiquitinated human ID complex bound to DNA, and reveal that it forms a closed ring that encircles the DNA. By comparison with the structure of the non-ubiquitinated ID complex bound to ICL DNA—which we also report here—we show that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures—together with biochemical data—indicate that the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. Our findings also reveal how monoubiquitination in general can induce an alternative protein structure with a new function.

DOI: 10.1038/s41586-020-2110-6

Source: https://www.nature.com/articles/s41586-020-2110-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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