INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée la Ligue contre le Cancer, Paris, France; University of Paris-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Genomic Vision, R&D Innovation Department, Bagneux, France.
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Rep. 2020 Dec 29;33(13):108559. doi: 10.1016/j.celrep.2020.108559.
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 (RAD50) 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 RAD50 impairs MRE11 nuclease activity. The corresponding mutation in Saccharomyces cerevisiae causes severe thermosensitive defects in both DNA repair and Tel1-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.
MRE11-RAD50-NBS1 复合物在应对 DNA 双链断裂中起着核心作用。在这里，我们发现了一名骨髓衰竭和发育缺陷的患者，其原因是 RAD50 基因的两个等位基因突变。其中一个突变导致无功能的纯合子缺失，而另一个突变（RAD50）导致 RAD50 卷曲螺旋域内的七肽重复序列中的单个残基丢失。该突变代表了一种人类 RAD50 功能分离突变，它会损害 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 RAD50 会损害 MRE11 核酸酶的活性。酿酒酵母中的相应突变会导致 DNA 修复和 Tel1 依赖性信号传导的严重热敏缺陷。这些发现表明，RAD50 卷曲螺旋中的微小七肽断裂足以阻碍人类和酵母中 MRE11 复合物的功能。此外，这些结果强调了 RAD50 卷曲螺旋在调节人类中 MRE11 依赖性 DNA 末端切除的重要性。
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