Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial
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Xavier Veaute
- Function : Author
- PersonId : 769773
- ORCID : 0000-0003-4868-247X
Didier Busso
- Function : Author
- PersonId : 758926
- ORCID : 0000-0003-3027-7900
Jean-Baptiste Charbonnier
- Function : Author
- PersonId : 758656
- ORCID : 0000-0002-5219-1983
- IdRef : 150171560
Stéphane Marcand
- Function : Author
- PersonId : 824362
- ORCID : 0000-0001-5199-1885
- IdRef : 186185790
Keunchil Park
- Function : Author
- PersonId : 764353
- ORCID : 0000-0002-4846-7449
Hidenobu Ishii
- Function : Author
Filippo de Marinis
- Function : Author
Aleksandra Szczesna
- Function : Author
Andreas Polychronis
- Function : Author
Ruchan Uslu
- Function : Author
Osvaldo Arén Frontera
- Function : Author
Huiling Xiong
- Function : Author
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 ( B locks A ddition of T elomeres) 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.