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10.3390/cells13161361
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Article

Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site

by
Claire Ghilain
1,
Olivia Vidal-Cruchez
2,
Aurélia Joly
3,
Michelle Debatisse
4,
Eric Gilson
1,5,6,7,* and
Marie-Josèphe Giraud-Panis
1,*
1
CNRS UMR7284/INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, University Côte d’Azur, 06107 Nice, France
2
Simpson Querrey Institute, 303 E Superior, Chicago, IL 60611, USA
3
Medical Microbiology and Immunology Department, Faculty of Medicine & Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2R3, Canada
4
Gustave Roussy Institute, Sorbonne Université, UPMC, 94805 Villejuif, France
5
Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
6
International Research Project in Hematology, Cancer and Aging, Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Ruijin Hospital, Shanghai Jiao Tong University School, Shanghai 200025, China
7
Department of Genetics, CHU, FHU OncoAge, 06000 Nice, France
*
Authors to whom correspondence should be addressed.
Cells 2024, 13(16), 1361; https://doi.org/10.3390/cells13161361
Submission received: 24 July 2024 / Revised: 9 August 2024 / Accepted: 14 August 2024 / Published: 15 August 2024
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Abstract

Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site.
Keywords: DNA topology; telomere; TRF2 DNA topology; telomere; TRF2

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MDPI and ACS Style

Ghilain, C.; Vidal-Cruchez, O.; Joly, A.; Debatisse, M.; Gilson, E.; Giraud-Panis, M.-J. Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site. Cells 2024, 13, 1361. https://doi.org/10.3390/cells13161361

AMA Style

Ghilain C, Vidal-Cruchez O, Joly A, Debatisse M, Gilson E, Giraud-Panis M-J. Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site. Cells. 2024; 13(16):1361. https://doi.org/10.3390/cells13161361

Chicago/Turabian Style

Ghilain, Claire, Olivia Vidal-Cruchez, Aurélia Joly, Michelle Debatisse, Eric Gilson, and Marie-Josèphe Giraud-Panis. 2024. "Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site" Cells 13, no. 16: 1361. https://doi.org/10.3390/cells13161361

APA Style

Ghilain, C., Vidal-Cruchez, O., Joly, A., Debatisse, M., Gilson, E., & Giraud-Panis, M.-J. (2024). Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site. Cells, 13(16), 1361. https://doi.org/10.3390/cells13161361

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