Mechanism of MRX inhibition by Rif2 at telomeres

Florian Roisné-Hamelin, Sabrina Pobiega, Kévin Jézéquel, Simona Miron, Jordane Dépagne, Xavier Veaute, Didier Busso, Marie-Hélène Le Du, Isabelle Callebaut, Jean-Baptiste Charbonnier, Philippe Cuniasse, Sophie Zinn-Justin and Stéphane Marcand ()
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Florian Roisné-Hamelin: iRCM, UMR Stabilité Génétique Cellules Souches et Radiations
Sabrina Pobiega: iRCM, UMR Stabilité Génétique Cellules Souches et Radiations
Kévin Jézéquel: iRCM, UMR Stabilité Génétique Cellules Souches et Radiations
Simona Miron: Institute for Integrative Biology of the Cell (I2BC)
Jordane Dépagne: UMR Stabilité Génétique Cellules Souches et Radiations
Xavier Veaute: UMR Stabilité Génétique Cellules Souches et Radiations
Didier Busso: UMR Stabilité Génétique Cellules Souches et Radiations
Marie-Hélène Le Du: Institute for Integrative Biology of the Cell (I2BC)
Isabelle Callebaut: Institut de Minéralogie de Physique des Matériaux et de Cosmochimie (IMPMC)
Jean-Baptiste Charbonnier: Institute for Integrative Biology of the Cell (I2BC)
Philippe Cuniasse: Institute for Integrative Biology of the Cell (I2BC)
Sophie Zinn-Justin: Institute for Integrative Biology of the Cell (I2BC)
Stéphane Marcand: iRCM, UMR Stabilité Génétique Cellules Souches et Radiations

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23035-w

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