A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans.
A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans.
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DOI：
10.1016/j.celrep.2020.108559
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发表时间：
2020-12-29
期刊：
影响因子：
8.8
通讯作者：
Revy P
中科院分区：
文献类型：
--
作者：
Chansel-Da Cruz M;Hohl M;Ceppi I;Kermasson L;Maggiorella L;Modesti M;de Villartay JP;Ileri T;Cejka P;Petrini JHJ;Revy P
MRE 11-RAD 50-NBS 1复合物在响应DNA双链断裂中起核心作用。在这里，我们确定了一个病人的骨髓衰竭和发育缺陷所造成的双等位基因的RAD 50突变。其中一个突变产生无效等位基因，而另一个突变（RAD 50 E1035 Δ）导致RAD 50卷曲螺旋结构域内七肽重复序列中单个残基的丢失。该突变代表了人RAD 50功能分离突变，其损害DNA修复、DNA复制和DNA末端切除，而不影响ATM依赖性DNA损伤反应。纯化的重组蛋白表明，RAD 50 E1035 Δ损害MRE 11核酸酶活性。酿酒酵母中的相应突变导致DNA修复和Tel 1ATM依赖性信号传导中的严重热敏性缺陷。这些发现表明，RAD 50卷曲螺旋中的微小七肽断裂足以阻碍人和酵母中的MRE 11复合物功能。此外，这些结果强调了RAD 50卷曲螺旋调节人类MRE 11依赖性DNA末端切除的重要性。人RAD 50突变体损害DNA修复，但不损害ATM依赖性DDR。单个氨基酸缺失破坏RAD 50的卷曲螺旋结构。提供证据表明，位于远离MRE 11相互作用界面的人RAD 50卷曲螺旋中的突变将MRN复合物的信号传导功能与其断裂的DNA末端加工活性解偶联。这证明了RAD 50卷曲螺旋在MRE 11复合物调节中的关键作用。
The MRE11-RAD50-NBS1 complex plays a central role in response to DNA double-strand breaks. Here, we identify a patient with bone marrow failure and developmental defects caused by biallelic RAD50 mutations. One of the mutations creates a null allele, whereas the other (RAD50E1035Δ) leads to the loss of a single residue in the heptad repeats within the RAD50 coiled-coil domain. This mutation represents a human RAD50 separation-of-function mutation that impairs DNA repair, DNA replication, and DNA end resection without affecting ATM-dependent DNA damage response. Purified recombinant proteins indicate that RAD50E1035Δ impairs MRE11 nuclease activity. The corresponding mutation in Saccharomyces cerevisiae causes severe thermosensitive defects in both DNA repair and Tel1ATM-dependent signaling. These findings demonstrate that a minor heptad break in the RAD50 coiled coil suffices to impede MRE11 complex functions in human and yeast. Furthermore, these results emphasize the importance of the RAD50 coiled coil to regulate MRE11-dependent DNA end resection in humans. A human RAD50 mutant impairs DNA repair but not ATM-dependent DDR A single amino acid deletion disrupts the coiled-coil structure of RAD50 A Rad50 mutant yeast strain exhibits an extremely severe thermosensitive phenotype Chansel-Da Cruz et al. provide evidence that a mutation in the human RAD50 coiled coil located away from the MRE11 interaction interface uncouples the signaling function of the MRN complex from its broken DNA end processing activities. This demonstrates the crucial role of the RAD50 coiled coil in the MRE11 complex regulation.
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影响因子：
64.5
作者：
Buis J;Wu Y;Deng Y;Leddon J;Westfield G;Eckersdorff M;Sekiguchi JM;Chang S;Ferguson DO
通讯作者：
Ferguson DO
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
5.8
作者：
Delorenzi, M;Speed, T
通讯作者：
Speed, T
影响因子：
4
作者：
Hopfner, Karl-Peter
通讯作者：
Hopfner, Karl-Peter
DOI：
10.1073/pnas.1820157116
发表时间：
2019-03-19
影响因子：
11.1
作者：
Cannavo, Elda;Reginato, Giordano;Cejka, Petr
通讯作者：
Cejka, Petr