Nuclear envelope dysfunction and its contribution to the aging process

Abstract

The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins’ alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina‐associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process.

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

“…KPNA4, SMC4, and CXXC4) [58,59,60]. SMC4 is known to inhibit cellular senescence in replicating cells [61,62]. Additional eQTL colocalization results for IEAA include CD46, a regulator of the complement system and T-cell function [63,64], and the lipid transporter gene ATP8B4, which contains variants that have been reported in relation to centenarian status in Italians and Alzheimer's disease [65,66].…”

Nuclear Morphology and the Biology of Cancer Cells

“…The ONM and INM are joined at nuclear pore complexes (NPCs) that are inserted into the phospholipid bilayers. NPCs are very large (>60 MDa in mammalian cells) protein complexes that regulate the directional transport of soluble molecules between the nucleus and the cytoplasm [9-11], and nucleoporins are one of their key components [4, 12]. Between the ONM and INM is a 30–50-nm wide perinuclear space that is contiguous with the space of the rough endoplasmatic reticulum.…”

“…Molecules of the NE including lamins and many NETs and NPCs serve as anchoring sites for chromatin [9-11, 34]. A- and B-type lamins bind to chromatin through interactions with INM proteins containing the LAP2-emerin-MAN1 domain [12]. Lamin B1 is mainly associated with heterochromatin [12].…”

“…A- and B-type lamins bind to chromatin through interactions with INM proteins containing the LAP2-emerin-MAN1 domain [12]. Lamin B1 is mainly associated with heterochromatin [12]. Many of these molecules influence heterochromatin assembly at the NE and can have an effect on gene positioning and gene expression [35].…”

“…The NETs and nuclear lamina recruit chromatin that has been modified with specific epigenetic marks, provide silencing factors that add new epigenetic modifications to genes located at the nuclear periphery, and sequester transcription factors away from the nuclear interior. Some chromatin-binding partners of NETs specifically reflect transcriptionally silenced chromatin [12]. On the other hand, transcriptionally active peripheral euchromatin tends to be associated with NPCs.…”