GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres

Human telomeres are composed of GGGTTA repeats and interspersed with variant repeats. The GGGCTA variant motif was identified in the proximal regions of human telomeres about 10 years ago and was shown to display a length-dependent instability. In parallel, a structural study showed that four GGGCTA...

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Main Authors: Chatain, Jean, Blond, Alain, Phan, Anh Tuân, Saintomé, Carole, Alberti, Patrizia
Other Authors: School of Physical and Mathematical Sciences
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Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/153717
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spelling sg-ntu-dr.10356-1537172023-02-28T19:38:11Z GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres Chatain, Jean Blond, Alain Phan, Anh Tuân Saintomé, Carole Alberti, Patrizia School of Physical and Mathematical Sciences NTU Institute of Structural Biology Science::Biological sciences Single-Stranded-DNA Werner-Syndrome Protein Human telomeres are composed of GGGTTA repeats and interspersed with variant repeats. The GGGCTA variant motif was identified in the proximal regions of human telomeres about 10 years ago and was shown to display a length-dependent instability. In parallel, a structural study showed that four GGGCTA repeats folded into a non-canonical G-quadruplex (G4) comprising a Watson-Crick GCGC tetrad. It was proposed that this non-canonical G4 might be an additional obstacle for telomere replication. In the present study, we demonstrate that longer GGGCTA arrays fold into G4 and into hairpins. We also demonstrate that replication protein A (RPA) efficiently binds to GGGCTA repeats structured into G4 but poorly binds to GGGCTA repeats structured into hairpins. Our results (along with results obtained with a more stable variant motif) suggest that GGGCTA hairpins are at the origin of GGGCTA length-dependent instability. They also suggest, as working hypothesis, that failure of efficient binding of RPA to GGGCTA structured into hairpins might be involved in the mechanism of GGGCTA array instability. On the basis of our present and past studies about telomeric G4 and their interaction with RPA, we propose an original point of view about telomeric G4 and the evolution of telomeric motifs. Published version Museum National d’Histoire Naturelle (MNHN); Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (INSERM); Ministere de l’Enseignement Superieur, de la Recherche de de l’Innovation (MESRI) Ph.D. Fellowship (to J.C.). Funding for open access charge: INSERM. 2022-01-17T07:23:20Z 2022-01-17T07:23:20Z 2021 Journal Article Chatain, J., Blond, A., Phan, A. T., Saintomé, C. & Alberti, P. (2021). GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres. Nucleic Acids Research, 49(13), 7588-7601. https://dx.doi.org/10.1093/nar/gkab518 0305-1048 https://hdl.handle.net/10356/153717 10.1093/nar/gkab518 34214172 2-s2.0-85112126981 13 49 7588 7601 en Nucleic Acids Research © 2021 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://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 application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Single-Stranded-DNA
Werner-Syndrome Protein
spellingShingle Science::Biological sciences
Single-Stranded-DNA
Werner-Syndrome Protein
Chatain, Jean
Blond, Alain
Phan, Anh Tuân
Saintomé, Carole
Alberti, Patrizia
GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres
description Human telomeres are composed of GGGTTA repeats and interspersed with variant repeats. The GGGCTA variant motif was identified in the proximal regions of human telomeres about 10 years ago and was shown to display a length-dependent instability. In parallel, a structural study showed that four GGGCTA repeats folded into a non-canonical G-quadruplex (G4) comprising a Watson-Crick GCGC tetrad. It was proposed that this non-canonical G4 might be an additional obstacle for telomere replication. In the present study, we demonstrate that longer GGGCTA arrays fold into G4 and into hairpins. We also demonstrate that replication protein A (RPA) efficiently binds to GGGCTA repeats structured into G4 but poorly binds to GGGCTA repeats structured into hairpins. Our results (along with results obtained with a more stable variant motif) suggest that GGGCTA hairpins are at the origin of GGGCTA length-dependent instability. They also suggest, as working hypothesis, that failure of efficient binding of RPA to GGGCTA structured into hairpins might be involved in the mechanism of GGGCTA array instability. On the basis of our present and past studies about telomeric G4 and their interaction with RPA, we propose an original point of view about telomeric G4 and the evolution of telomeric motifs.
author2 School of Physical and Mathematical Sciences
author_facet School of Physical and Mathematical Sciences
Chatain, Jean
Blond, Alain
Phan, Anh Tuân
Saintomé, Carole
Alberti, Patrizia
format Article
author Chatain, Jean
Blond, Alain
Phan, Anh Tuân
Saintomé, Carole
Alberti, Patrizia
author_sort Chatain, Jean
title GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres
title_short GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres
title_full GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres
title_fullStr GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres
title_full_unstemmed GGGCTA repeats can fold into hairpins poorly unfolded by replication protein A : a possible origin of the length-dependent instability of GGGCTA variant repeats in human telomeres
title_sort gggcta repeats can fold into hairpins poorly unfolded by replication protein a : a possible origin of the length-dependent instability of gggcta variant repeats in human telomeres
publishDate 2022
url https://hdl.handle.net/10356/153717
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