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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2018
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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. |
format | Online Article Text |
id | pubmed-5994899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
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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