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 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.

Progerin triggers a phenotypic switch in vascular smooth muscle cells that causes replication stress and an aging-associated secretory signature

“…There is robust evidence that progerin expression hinders telomere function, including a decrease in telomere length and increased telomere damage. As testament of the importance of telomere dysfunction driving HGPS phenotype, ectopic expression of telomerase rescues telomere damage, inhibits the DNA damage response at telomeres, improves HGPS cellular phenotypes, and extends lifespan in progeria mice (Aguado et al, 2019; Kychygina et al, 2021; Li et al, 2019).…”

“…In fact, we show that progerin induces telomere fragility and cell death. Different lines of evidence stress the importance to preserve nuclear envelope integrity, and in HGPS this organization is perturbed, causing depletion of the dNTP pools and telomere dysfunction (Kychygina et al, 2021). In addition, deficiencies on telomere capping proteins such as TRF1 induce telomere dysfunction in progeria and other models (Berti et al, 2013; Cao et al, 2011; McCord et al, 2013).…”

“…At the cellular level, unresolved or unrepaired DNA damage and genomic instability are potent inducers of cell death. Extensive evidence links progerin expression with DNA damage, DNA repair deficiencies, and telomere and mitochondrial dysfunction in different cellular models, including vascular cells (Aguado et al, 2019; Cao et al, 2011; Chojnowski et al, 2015; Coll-Bonfill et al, 2020; Kreienkamp et al, 2018; Kychygina et al, 2021). It is likely that genomic instability contributes to the manifestation of the drastic VSMC loss and CVD in HGPS.…”

“…It is likely that genomic instability contributes to the manifestation of the drastic VSMC loss and CVD in HGPS. For instance, mitochondrial dysfunction and telomeric damage promote VSMC senescence, vessel inflammation, and stiffness (Canugovi et al, 2019; Kychygina et al, 2021; Y. Liu et al, 2013; Y.-F. Liu et al, 2020).…”

Methylation of Subtelomeric Chromatin Modifies the Expression of the lncRNA TERRA, Disturbing Telomere Homeostasis

“…Apart from the direct effect that the chromatin can have on the expression of TERRA, the epigenetic changes that were evidenced in our results could further impact telomere homeostasis at a structural level. It is well known how the spatial localization of the chromatin can impact genome stability and gene regulation [ 71 ]; in the same way, chromatin folding and chromatin domain integrity can impact the epigenome by maintaining the topological homeostasis of a cell [ 72 ]. Cancer, however, is characterized by altered gene expression, genome instability and epigenetic deregulation; these interconnected changes are associated with a robust alteration of the three-dimensional (3D) chromosomal organization that takes place during the initiation and progression stages of carcinogenesis [ 72 , 73 , 74 ].…”