Rap1-mediated steric hindrance protects telomeres from MRX sensing
Abstract
Telomere capping largely depends on telomere length. Abnormally short telomeres are prone to activate DNA damage checkpoint, undergo unscheduled chromosomal fusions through nonhomologous end-joining (NHEJ) and be resected. All these processes are mediated by the Mre11–Rad50–Xrs2NBS1 (MRXMRN) complex. The response to telomere length is thought to correlate with the number of DNA-bound telomeric proteins but the mechanisms translating this number into functional protection remain unclear. Here, combining genetic and reconstitution biochemistry approaches, we explain why NHEJ inhibition and DNA resection suppression are proportional to the length of Rap1-bound arrays adjacent to DNA ends in Saccharomyces cerevisiae. Our findings reveal that MRX has a capacity to distinguish short from long protein blocks at DNA breaks, which translates into the ability of Rap1 protein–DNA arrays to suppress MRX on the basis of their length. Unlike the previously described direct inhibition of MRXMRN by Rif2 and TRF2 iDDR, the process described here does not rely on direct protein–protein interactions. Instead, Rap1 inhibits MRX by steric hindrance, determined both by the length of DNA it shields and by the coverage density. These results explain how cells detect short telomeres, a crucial process for telomere length homeostasis and telomere-driven senescence. The authors show that Rap1 protein coverage protects telomeres by physically blocking the Mre11–Rad50–Xrs2NBS1 complex. Longer, denser Rap1 arrays better prevent DNA damage responses, providing a mechanism for how cells detect short telomeres and maintain genome stability
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BibTeX
@article{mattarocci2026rap1mediated,
title = {{Rap1-mediated steric hindrance protects telomeres from MRX sensing}},
author = {Stefano Mattarocci and Giordano Reginato and Elda Cannavo and Florian Roisné-Hamelin and Robert Gnügge and Alice Deshayes and Sabrina Pobiega and Olivier Alibert and Vincent Morin and Virginie Ropars and Johannes Mehringer and Vincent Geli and Philippe Cuniasse and Jean-Baptiste Charbonnier and Lorraine Symington and Petr Cejka and Stéphane Marcand},
journal = {Nature Structural and Molecular Biology},
year = {2026},
month = may,
doi = {10.1038/s41594-026-01810-x},
url = {https://hal.science/hal-05855028v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Rap1-mediated steric hindrance protects telomeres from MRX sensing
AU - Stefano Mattarocci
AU - Giordano Reginato
AU - Elda Cannavo
AU - Florian Roisné-Hamelin
AU - Robert Gnügge
AU - Alice Deshayes
AU - Sabrina Pobiega
AU - Olivier Alibert
AU - Vincent Morin
AU - Virginie Ropars
AU - Johannes Mehringer
AU - Vincent Geli
AU - Philippe Cuniasse
AU - Jean-Baptiste Charbonnier
AU - Lorraine Symington
AU - Petr Cejka
AU - Stéphane Marcand
PY - 2026
DA - 2026/05/20
JO - Nature Structural and Molecular Biology
DO - 10.1038/s41594-026-01810-x
UR - https://hal.science/hal-05855028v1
AB - Telomere capping largely depends on telomere length. Abnormally short telomeres are prone to activate DNA damage checkpoint, undergo unscheduled chromosomal fusions through nonhomologous end-joining (NHEJ) and be resected. All these processes are mediated by the Mre11–Rad50–Xrs2NBS1 (MRXMRN) complex. The response to telomere length is thought to correlate with the number of DNA-bound telomeric proteins but the mechanisms translating this number into functional protection remain unclear. Here, combining genetic and reconstitution biochemistry approaches, we explain why NHEJ inhibition and DNA resection suppression are proportional to the length of Rap1-bound arrays adjacent to DNA ends in Saccharomyces cerevisiae. Our findings reveal that MRX has a capacity to distinguish short from long protein blocks at DNA breaks, which translates into the ability of Rap1 protein–DNA arrays to suppress MRX on the basis of their length. Unlike the previously described direct inhibition of MRXMRN by Rif2 and TRF2 iDDR, the process described here does not rely on direct protein–protein interactions. Instead, Rap1 inhibits MRX by steric hindrance, determined both by the length of DNA it shields and by the coverage density. These results explain how cells detect short telomeres, a crucial process for telomere length homeostasis and telomere-driven senescence. The authors show that Rap1 protein coverage protects telomeres by physically blocking the Mre11–Rad50–Xrs2NBS1 complex. Longer, denser Rap1 arrays better prevent DNA damage responses, providing a mechanism for how cells detect short telomeres and maintain genome stability
SN - 1545-9993
SN - 1545-9985
ER -