Academic Journal
Structural and functional basis of inositol hexaphosphate stimulation of NHEJ through stabilization of Ku-XLF interaction
| العنوان: | Structural and functional basis of inositol hexaphosphate stimulation of NHEJ through stabilization of Ku-XLF interaction |
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| المؤلفون: | Kefala Stavridi, Antonia, Gontier, Amandine, Morin, Vincent, Frit, Philippe, Ropars, Virginie, Barboule, Nadia, Racca, Carine, Jonchhe, Sagun, Morten, Michael J, Andreani, Jessica, Rak, Alexey, Legrand, Pierre, Bourand-Plantefol, Alexa, Hardwick, Steven W, Chirgadze, Dimitri Y, Davey, Paul, de Oliveira, Taiana Maia, Rothenberg, Eli, Britton, Sebastien, Calsou, Patrick, Blundell, Tom L, Varela, Paloma F, Chaplin, Amanda K, Charbonnier, Jean-Baptiste |
| المساهمون: | Department of Biochemistry, University of Cambridge, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Sanofi Vitry-sur-Seine, SANOFI Recherche, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Astra Zeneca R&D, Department of Molecular and Cell Biology Leicester, University of Leicester, ANR-17-CE12-0020,NHEJLIG4,DYNAMIQUE ET STRUCTURE DE LA MACHINERIE c-NHEJ: RÔLES PIVOTS DE L'ADN LIGASE 4 HUMAINE(2017), ANR-20-CE11-0026,BreakDance,Caractérisation de la chorégraphie orchestrée par l'hétérodimère Ku sur les cassures double-brin de l'ADN(2020), ANR-21-CE12-0019,CURE,Elimination programmée d'ADN chez un unicellulaire modèle : coordination entre coupure de l'ADN et réparation des cassures double-brin(2021) |
| المصدر: | ISSN: 0305-1048. |
| بيانات النشر: | HAL CCSD Oxford University Press |
| سنة النشر: | 2023 |
| المجموعة: | Université Toulouse III - Paul Sabatier: HAL-UPS |
| مصطلحات موضوعية: | [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; The classical Non-Homologous End Joining (c-NHEJ) pathway is the predominant process in mammals for repairing endogenous, accidental or programmed DNA Double-Strand Breaks. c-NHEJ is regulated by several accessory factors, post-translational modifications, endogenous chemical agents and metabolites. The metabolite inositol-hexaphosphate (IP6) stimulates c-NHEJ by interacting with the Ku70–Ku80 heterodimer (Ku). We report cryo-EM structures of apo- and DNA-bound Ku in complex with IP6, at 3.5 Å and 2.74 Å resolutions respectively, and an X-ray crystallography structure of a Ku in complex with DNA and IP6 at 3.7 Å. The Ku-IP6 interaction is mediated predominantly via salt bridges at the interface of the Ku70 and Ku80 subunits. This interaction is distant from the DNA, DNA-PKcs, APLF and PAXX binding sites and in close proximity to XLF binding site. Biophysical experiments show that IP6 binding increases the thermal stability of Ku by 2°C in a DNA-dependent manner, stabilizes Ku on DNA and enhances XLF affinity for Ku. In cells, selected mutagenesis of the IP6 binding pocket reduces both Ku accrual at damaged sites and XLF enrolment in the NHEJ complex, which translate into a lower end-joining efficiency. Thus, this study defines the molecular bases of the IP6 metabolite stimulatory effect on the c-NHEJ repair activity. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | hal-04284601; https://hal.science/hal-04284601; https://hal.science/hal-04284601/document; https://hal.science/hal-04284601/file/gkad863%20%281%29.pdf |
| DOI: | 10.1093/nar/gkad863 |
| الاتاحة: | https://hal.science/hal-04284601 https://hal.science/hal-04284601/document https://hal.science/hal-04284601/file/gkad863%20%281%29.pdf https://doi.org/10.1093/nar/gkad863 |
| Rights: | http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.CB348F82 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/nar/gkad863 |
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