Cargando…

Mechanism of MRX inhibition by Rif2 at telomeres

Specific proteins present at telomeres ensure chromosome end stability, in large part through unknown mechanisms. In this work, we address how the Saccharomyces cerevisiae ORC-related Rif2 protein protects telomere. We show that the small N-terminal Rif2 BAT motif (Blocks Addition of Telomeres) prev...

Descripción completa

Detalles Bibliográficos
Autores principales: Roisné-Hamelin, Florian, Pobiega, Sabrina, Jézéquel, Kévin, Miron, Simona, Dépagne, Jordane, Veaute, Xavier, Busso, Didier, Du, Marie-Hélène Le, Callebaut, Isabelle, Charbonnier, Jean-Baptiste, Cuniasse, Philippe, Zinn-Justin, Sophie, Marcand, Stéphane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115599/
https://www.ncbi.nlm.nih.gov/pubmed/33980827
http://dx.doi.org/10.1038/s41467-021-23035-w
_version_ 1783691230904844288
author Roisné-Hamelin, Florian
Pobiega, Sabrina
Jézéquel, Kévin
Miron, Simona
Dépagne, Jordane
Veaute, Xavier
Busso, Didier
Du, Marie-Hélène Le
Callebaut, Isabelle
Charbonnier, Jean-Baptiste
Cuniasse, Philippe
Zinn-Justin, Sophie
Marcand, Stéphane
author_facet Roisné-Hamelin, Florian
Pobiega, Sabrina
Jézéquel, Kévin
Miron, Simona
Dépagne, Jordane
Veaute, Xavier
Busso, Didier
Du, Marie-Hélène Le
Callebaut, Isabelle
Charbonnier, Jean-Baptiste
Cuniasse, Philippe
Zinn-Justin, Sophie
Marcand, Stéphane
author_sort Roisné-Hamelin, Florian
collection PubMed
description Specific proteins present at telomeres ensure chromosome end stability, in large part through unknown mechanisms. In this work, we address how the Saccharomyces cerevisiae ORC-related Rif2 protein protects telomere. We show that the small N-terminal Rif2 BAT motif (Blocks Addition of Telomeres) previously known to limit telomere elongation and Tel1 activity is also sufficient to block NHEJ and 5’ end resection. The BAT motif inhibits the ability of the Mre11-Rad50-Xrs2 complex (MRX) to capture DNA ends. It acts through a direct contact with Rad50 ATP-binding Head domains. Through genetic approaches guided by structural predictions, we identify residues at the surface of Rad50 that are essential for the interaction with Rif2 and its inhibition. Finally, a docking model predicts how BAT binding could specifically destabilise the DNA-bound state of the MRX complex. From these results, we propose that when an MRX complex approaches a telomere, the Rif2 BAT motif binds MRX Head in its ATP-bound resting state. This antagonises MRX transition to its DNA-bound state, and favours a rapid return to the ATP-bound state. Unable to stably capture the telomere end, the MRX complex cannot proceed with the subsequent steps of NHEJ, Tel1-activation and 5’ resection.
format Online
Article
Text
id pubmed-8115599
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-81155992021-05-14 Mechanism of MRX inhibition by Rif2 at telomeres Roisné-Hamelin, Florian Pobiega, Sabrina Jézéquel, Kévin Miron, Simona Dépagne, Jordane Veaute, Xavier Busso, Didier Du, Marie-Hélène Le Callebaut, Isabelle Charbonnier, Jean-Baptiste Cuniasse, Philippe Zinn-Justin, Sophie Marcand, Stéphane Nat Commun Article Specific proteins present at telomeres ensure chromosome end stability, in large part through unknown mechanisms. In this work, we address how the Saccharomyces cerevisiae ORC-related Rif2 protein protects telomere. We show that the small N-terminal Rif2 BAT motif (Blocks Addition of Telomeres) previously known to limit telomere elongation and Tel1 activity is also sufficient to block NHEJ and 5’ end resection. The BAT motif inhibits the ability of the Mre11-Rad50-Xrs2 complex (MRX) to capture DNA ends. It acts through a direct contact with Rad50 ATP-binding Head domains. Through genetic approaches guided by structural predictions, we identify residues at the surface of Rad50 that are essential for the interaction with Rif2 and its inhibition. Finally, a docking model predicts how BAT binding could specifically destabilise the DNA-bound state of the MRX complex. From these results, we propose that when an MRX complex approaches a telomere, the Rif2 BAT motif binds MRX Head in its ATP-bound resting state. This antagonises MRX transition to its DNA-bound state, and favours a rapid return to the ATP-bound state. Unable to stably capture the telomere end, the MRX complex cannot proceed with the subsequent steps of NHEJ, Tel1-activation and 5’ resection. Nature Publishing Group UK 2021-05-12 /pmc/articles/PMC8115599/ /pubmed/33980827 http://dx.doi.org/10.1038/s41467-021-23035-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Roisné-Hamelin, Florian
Pobiega, Sabrina
Jézéquel, Kévin
Miron, Simona
Dépagne, Jordane
Veaute, Xavier
Busso, Didier
Du, Marie-Hélène Le
Callebaut, Isabelle
Charbonnier, Jean-Baptiste
Cuniasse, Philippe
Zinn-Justin, Sophie
Marcand, Stéphane
Mechanism of MRX inhibition by Rif2 at telomeres
title Mechanism of MRX inhibition by Rif2 at telomeres
title_full Mechanism of MRX inhibition by Rif2 at telomeres
title_fullStr Mechanism of MRX inhibition by Rif2 at telomeres
title_full_unstemmed Mechanism of MRX inhibition by Rif2 at telomeres
title_short Mechanism of MRX inhibition by Rif2 at telomeres
title_sort mechanism of mrx inhibition by rif2 at telomeres
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115599/
https://www.ncbi.nlm.nih.gov/pubmed/33980827
http://dx.doi.org/10.1038/s41467-021-23035-w
work_keys_str_mv AT roisnehamelinflorian mechanismofmrxinhibitionbyrif2attelomeres
AT pobiegasabrina mechanismofmrxinhibitionbyrif2attelomeres
AT jezequelkevin mechanismofmrxinhibitionbyrif2attelomeres
AT mironsimona mechanismofmrxinhibitionbyrif2attelomeres
AT depagnejordane mechanismofmrxinhibitionbyrif2attelomeres
AT veautexavier mechanismofmrxinhibitionbyrif2attelomeres
AT bussodidier mechanismofmrxinhibitionbyrif2attelomeres
AT dumariehelenele mechanismofmrxinhibitionbyrif2attelomeres
AT callebautisabelle mechanismofmrxinhibitionbyrif2attelomeres
AT charbonnierjeanbaptiste mechanismofmrxinhibitionbyrif2attelomeres
AT cuniassephilippe mechanismofmrxinhibitionbyrif2attelomeres
AT zinnjustinsophie mechanismofmrxinhibitionbyrif2attelomeres
AT marcandstephane mechanismofmrxinhibitionbyrif2attelomeres