A disease-causing single amino acid deletion in the coiled-coil domain of RAD50 impairs MRE11 complex functions in yeast and humans Journal Article
| Authors: | Chansel-Da Cruz, M.; Hohl, M.; Ceppi, I.; Kermasson, L.; Maggiorella, L.; Modesti, M.; de Villartay, J. P.; Ileri, T.; Cejka, P.; Petrini, J. H. J.; Revy, P. |
| Article Title: | A disease-causing single amino acid deletion in the coiled-coil domain of RAD50 impairs MRE11 complex functions in yeast and humans |
| Abstract: | 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. © 2020 The Author(s) 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. © 2020 The Author(s) |
| Keywords: | mre11; rad50; dna repair; nuclease activity; replication; immunodeficiency; coiled-coil; mrn |
| Journal Title: | Cell Reports |
| Volume: | 33 |
| Issue: | 13 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2020-12-29 |
| Start Page: | 108559 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2020.108559 |
| PUBMED: | 33378670 |
| PROVIDER: | scopus |
| PMCID: | PMC7788285 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2021 -- Source: Scopus |
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