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TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress

Telomeres are intrinsically difficult-to-replicate region of eukaryotic chromosomes. Telomeric repeat binding factor 2 (TRF2) binds to origin recognition complex (ORC) to facilitate the loading of ORC and the replicative helicase MCM complex onto DNA at telomeres. However, the biological significanc...

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Autores principales: Higa, Mitsunori, Matsuda, Yukihiro, Fujii, Jumpei, Sugimoto, Nozomi, Yoshida, Kazumasa, Fujita, Masatoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643664/
https://www.ncbi.nlm.nih.gov/pubmed/34761263
http://dx.doi.org/10.1093/nar/gkab1004
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author Higa, Mitsunori
Matsuda, Yukihiro
Fujii, Jumpei
Sugimoto, Nozomi
Yoshida, Kazumasa
Fujita, Masatoshi
author_facet Higa, Mitsunori
Matsuda, Yukihiro
Fujii, Jumpei
Sugimoto, Nozomi
Yoshida, Kazumasa
Fujita, Masatoshi
author_sort Higa, Mitsunori
collection PubMed
description Telomeres are intrinsically difficult-to-replicate region of eukaryotic chromosomes. Telomeric repeat binding factor 2 (TRF2) binds to origin recognition complex (ORC) to facilitate the loading of ORC and the replicative helicase MCM complex onto DNA at telomeres. However, the biological significance of the TRF2–ORC interaction for telomere maintenance remains largely elusive. Here, we employed a TRF2 mutant with mutations in two acidic acid residues (E111A and E112A) that inhibited the TRF2–ORC interaction in human cells. The TRF2 mutant was impaired in ORC recruitment to telomeres and showed increased replication stress-associated telomeric DNA damage and telomere instability. Furthermore, overexpression of an ORC1 fragment (amino acids 244–511), which competitively inhibited the TRF2–ORC interaction, increased telomeric DNA damage under replication stress conditions. Taken together, these findings suggest that TRF2-mediated ORC recruitment contributes to the suppression of telomere instability.
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spelling pubmed-86436642021-12-06 TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress Higa, Mitsunori Matsuda, Yukihiro Fujii, Jumpei Sugimoto, Nozomi Yoshida, Kazumasa Fujita, Masatoshi Nucleic Acids Res Genome Integrity, Repair and Replication Telomeres are intrinsically difficult-to-replicate region of eukaryotic chromosomes. Telomeric repeat binding factor 2 (TRF2) binds to origin recognition complex (ORC) to facilitate the loading of ORC and the replicative helicase MCM complex onto DNA at telomeres. However, the biological significance of the TRF2–ORC interaction for telomere maintenance remains largely elusive. Here, we employed a TRF2 mutant with mutations in two acidic acid residues (E111A and E112A) that inhibited the TRF2–ORC interaction in human cells. The TRF2 mutant was impaired in ORC recruitment to telomeres and showed increased replication stress-associated telomeric DNA damage and telomere instability. Furthermore, overexpression of an ORC1 fragment (amino acids 244–511), which competitively inhibited the TRF2–ORC interaction, increased telomeric DNA damage under replication stress conditions. Taken together, these findings suggest that TRF2-mediated ORC recruitment contributes to the suppression of telomere instability. Oxford University Press 2021-11-11 /pmc/articles/PMC8643664/ /pubmed/34761263 http://dx.doi.org/10.1093/nar/gkab1004 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Higa, Mitsunori
Matsuda, Yukihiro
Fujii, Jumpei
Sugimoto, Nozomi
Yoshida, Kazumasa
Fujita, Masatoshi
TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress
title TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress
title_full TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress
title_fullStr TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress
title_full_unstemmed TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress
title_short TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress
title_sort trf2-mediated orc recruitment underlies telomere stability upon dna replication stress
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643664/
https://www.ncbi.nlm.nih.gov/pubmed/34761263
http://dx.doi.org/10.1093/nar/gkab1004
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