Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial - Archive ouverte HAL Access content directly
Journal Articles Journal of Thoracic Oncology Year : 2021

Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial

(1) , (1) , (1) , (2) , (1) , (1) , (1) , (2) , (3) , (2) , (2) , (2) , (1) , (4) , (5) , (6) , (7) , (8) , , (9) , , , , , (10) , (11) , (12) , , , (13) , (13) , (14, 15)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Xavier Veaute
Didier Busso
Stéphane Marcand
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.

Dates and versions

hal-03627353 , version 1 (01-04-2022)

Identifiers

Cite

Florian Roisné-Hamelin, Sabrina Pobiega, Kévin Jézéquel, Simona Miron, Jordane Dépagne, et al.. Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial. Journal of Thoracic Oncology, 2021, 16 (8), pp.1369-1378. ⟨10.1016/j.jtho.2021.03.009⟩. ⟨hal-03627353⟩
18 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More