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

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...

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Autores principales: Limbo, Oliver, Yamada, Yoshiki, Russell, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994899/
https://www.ncbi.nlm.nih.gov/pubmed/29851556
http://dx.doi.org/10.1091/mbc.E17-07-0470
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author Limbo, Oliver
Yamada, Yoshiki
Russell, Paul
author_facet Limbo, Oliver
Yamada, Yoshiki
Russell, Paul
author_sort Limbo, Oliver
collection PubMed
description 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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spelling pubmed-59948992018-08-16 Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1 Limbo, Oliver Yamada, Yoshiki Russell, Paul Mol Biol Cell Articles 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. The American Society for Cell Biology 2018-06-01 /pmc/articles/PMC5994899/ /pubmed/29851556 http://dx.doi.org/10.1091/mbc.E17-07-0470 Text en © 2018 Limbo et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0/ This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Limbo, Oliver
Yamada, Yoshiki
Russell, Paul
Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
title Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
title_full Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
title_fullStr Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
title_full_unstemmed Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
title_short Mre11-Rad50–dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1
title_sort mre11-rad50–dependent activity of atm/tel1 at dna breaks and telomeres in the absence of nbs1
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994899/
https://www.ncbi.nlm.nih.gov/pubmed/29851556
http://dx.doi.org/10.1091/mbc.E17-07-0470
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