Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis
Abstract The MRE11-RAD50-NBS1/Xrs2 (MRN/X) protein complex has essential roles in the repair of damaged DNA. The current understanding of the conformational landscape of the core MR complex comes from various structural studies. However, given the heterogeneous nature of these structures, we suspect...
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Nature Portfolio
2025-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08003-0 |
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| author | Marella D. Canny Mahtab Beikzadeh Navneet Kaur Rohan Pendse Michael P. Latham |
| author_facet | Marella D. Canny Mahtab Beikzadeh Navneet Kaur Rohan Pendse Michael P. Latham |
| author_sort | Marella D. Canny |
| collection | DOAJ |
| description | Abstract The MRE11-RAD50-NBS1/Xrs2 (MRN/X) protein complex has essential roles in the repair of damaged DNA. The current understanding of the conformational landscape of the core MR complex comes from various structural studies. However, given the heterogeneous nature of these structures, we suspect that several conformational states may still be unaccounted for. Here, we use methyl-based NMR experiments on P. furiosus MR to determine an ensemble of distinct conformations of MR bound to DNA, consistent with the highly dynamic nature of the MR-DNA complex. Interrogation of these structures via in vitro activity assays on MR mutants reveal an unexpected, striking correlation between the nuclease activity of Mre11 and the magnitude of DNA-stimulated ATP hydrolysis by Rad50. Together, the structures and activity data support a model for MR activity where DNA-stimulated ATP hydrolysis unlocks Rad50 to provide access to the Mre11 active sites and further demonstrate how a heterogeneous ensemble of conformations can be used to coordinate various functions to direct biological outcomes. By elucidating the dynamic conformations of the DNA-bound MR complex, this work lays the foundation for future studies aimed at further characterizing this landscape and dissecting its role in the molecular mechanism of DNA repair and genome stability. |
| format | Article |
| id | doaj-art-1490f4899adf4d1f8d4bce6ad4df160b |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-1490f4899adf4d1f8d4bce6ad4df160b2025-08-20T02:25:41ZengNature PortfolioCommunications Biology2399-36422025-04-018111710.1038/s42003-025-08003-0Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysisMarella D. Canny0Mahtab Beikzadeh1Navneet Kaur2Rohan Pendse3Michael P. Latham4Department of Biochemistry, Molecular Biology, and Biophysics, University of MinnesotaDepartment of Chemistry and Biochemistry, Texas Tech UniversityDepartment of Chemistry and Biochemistry, Texas Tech UniversityDepartment of Chemistry and Biochemistry, Texas Tech UniversityDepartment of Biochemistry, Molecular Biology, and Biophysics, University of MinnesotaAbstract The MRE11-RAD50-NBS1/Xrs2 (MRN/X) protein complex has essential roles in the repair of damaged DNA. The current understanding of the conformational landscape of the core MR complex comes from various structural studies. However, given the heterogeneous nature of these structures, we suspect that several conformational states may still be unaccounted for. Here, we use methyl-based NMR experiments on P. furiosus MR to determine an ensemble of distinct conformations of MR bound to DNA, consistent with the highly dynamic nature of the MR-DNA complex. Interrogation of these structures via in vitro activity assays on MR mutants reveal an unexpected, striking correlation between the nuclease activity of Mre11 and the magnitude of DNA-stimulated ATP hydrolysis by Rad50. Together, the structures and activity data support a model for MR activity where DNA-stimulated ATP hydrolysis unlocks Rad50 to provide access to the Mre11 active sites and further demonstrate how a heterogeneous ensemble of conformations can be used to coordinate various functions to direct biological outcomes. By elucidating the dynamic conformations of the DNA-bound MR complex, this work lays the foundation for future studies aimed at further characterizing this landscape and dissecting its role in the molecular mechanism of DNA repair and genome stability.https://doi.org/10.1038/s42003-025-08003-0 |
| spellingShingle | Marella D. Canny Mahtab Beikzadeh Navneet Kaur Rohan Pendse Michael P. Latham Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis Communications Biology |
| title | Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis |
| title_full | Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis |
| title_fullStr | Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis |
| title_full_unstemmed | Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis |
| title_short | Dynamic conformations of the P. furiosus MR-DNA complex link Mre11 nuclease activity to DNA-stimulated Rad50 ATP hydrolysis |
| title_sort | dynamic conformations of the p furiosus mr dna complex link mre11 nuclease activity to dna stimulated rad50 atp hydrolysis |
| url | https://doi.org/10.1038/s42003-025-08003-0 |
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