Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools

Abstract Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuc...

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Autores principales:	Anna Kychygina, Marina Dall’Osto, Joshua A. M. Allen, Jean-Charles Cadoret, Vincent Piras, Hilda A. Pickett, Laure Crabbe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fd8ee578e2dc4197920ea343d1d04b53
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spelling	oai:doaj.org-article:fd8ee578e2dc4197920ea343d1d04b532021-12-02T18:02:43ZProgerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools10.1038/s41598-021-92631-z2045-2322https://doaj.org/article/fd8ee578e2dc4197920ea343d1d04b532021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92631-zhttps://doaj.org/toc/2045-2322Abstract Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.Anna KychyginaMarina Dall’OstoJoshua A. M. AllenJean-Charles CadoretVincent PirasHilda A. PickettLaure CrabbeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Kychygina Marina Dall’Osto Joshua A. M. Allen Jean-Charles Cadoret Vincent Piras Hilda A. Pickett Laure Crabbe Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools
description	Abstract Chromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.
format	article
author	Anna Kychygina Marina Dall’Osto Joshua A. M. Allen Jean-Charles Cadoret Vincent Piras Hilda A. Pickett Laure Crabbe
author_facet	Anna Kychygina Marina Dall’Osto Joshua A. M. Allen Jean-Charles Cadoret Vincent Piras Hilda A. Pickett Laure Crabbe
author_sort	Anna Kychygina
title	Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools
title_short	Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools
title_full	Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools
title_fullStr	Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools
title_full_unstemmed	Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools
title_sort	progerin impairs 3d genome organization and induces fragile telomeres by limiting the dntp pools
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fd8ee578e2dc4197920ea343d1d04b53
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Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools

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