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

Author:

Chatain Jean1,Blond Alain2,Phan Anh Tuân34ORCID,Saintomé Carole15ORCID,Alberti Patrizia1ORCID

Affiliation:

1. Laboratoire Structure et Instabilité des Génomes (StrInG), Muséum national d’Histoire naturelle, CNRS, Inserm, Paris 75005, France

2. Laboratoire Molécules de Communication et Adaptation des Microorganismes (MCAM), Muséum national d’Histoire naturelle, CNRS, Paris 75005, France

3. School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore

4. NTU Institute of Structural Biology, Nanyang Technological University, Singapore 636921, Singapore

5. Sorbonne Université, UFR927, Paris 75005, France

Abstract

Abstract 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.

Funder

Muséum National d’Histoire Naturelle

Centre National de la Recherche Scientifique

Institut National de la Santé et de la Recherche Médicale

Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference67 articles.

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4. Replication of the linear mitochondrial DNA of Tetrahymena pyriformis;Goldbach;Biochim. Biophys. Acta,1979

5. T-loops and the origin of telomeres;de Lange;Nat. Rev. Mol. Cell Biol.,2004

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