Open AccessMre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
Author(s) -
Oliver Limbo,
Yoshiki Yamada,
Paul Russell
Publication year - 2018
Publication title -
molecular biology of the cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.463
H-Index - 225
eISSN - 1939-4586
pISSN - 1059-1524
DOI - 10.1091/mbc.e17-07-0470
Subject(s) - rad50 , telomere , biology , microbiology and biotechnology , dna repair , dna damage , nijmegen breakage syndrome , dna , dna binding protein , genetics , transcription factor , gene , ataxia telangiectasia
The Mre11-Rad50-Nbs1 (MRN) protein complex and ATM/Tel1 kinase protect genome integrity through their functions in DNA double-strand break (DSB) repair, checkpoint signaling, and telomere maintenance. Nbs1 has a conserved C-terminal motif that binds ATM/Tel1, but the full extent and significance of ATM/Tel1 interactions with MRN are unknown. Here, we show that Tel1 overexpression bypasses the requirement for Nbs1 in DNA damage signaling and telomere maintenance. These activities require Mre11-Rad50, which localizes to DSBs and bind Tel1 in the absence of Nbs1. Fusion of the Tel1-binding motif of Nbs1 to Mre11 is sufficient to restore Tel1 signaling in nbs1Δ cells. Tel1 overexpression does not restore Tel1 signaling in cells carrying the rad50-I1192W mutation, which impairs the ability of Mre11-Rad50 to form the ATP-bound closed conformation. From these findings, we propose that Tel1 has a high-affinity interaction with the C-terminus of Nbs1 and a low-affinity association with Mre11-Rad50, which together accomplish efficient localization and activation of Tel1 at DSBs and telomeres.