Mre11-Rad50-dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1

Molecular Biology of the Cell
Oliver LimboPaul Russell

Abstract

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.

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Citations

Jan 31, 2019·Nucleic Acids Research·Corinne CassaniMaria Pia Longhese
Feb 13, 2019·International Journal of Molecular Sciences·Sergey S ShishkinKsenia Lisitskaya
Jan 16, 2020·Genes·Hannah M HyltonRuben C Petreaca
Mar 29, 2020·Biochemical Society Transactions·Chiara Vittoria ColomboMaria Pia Longhese
Dec 7, 2018·Genes·Julyun Oh, Lorraine S Symington
Jan 19, 2020·Nature Communications·Hisashi TatebeAsako Furukohri
Mar 7, 2021·Cells·Isadora Carolina Betim PavanJörg Kobarg

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Methods Mentioned

BETA
dissection
ChIP
PCR
immunoprecipitation
coimmunoprecipitation
pull downs
gel filtration

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