Abstract
Nucleocytoplasmic trafficking (NCT) of macromolecules is a fundamental process in eukaryotes that requires tight controls to maintain proper cell functions. Downregulation of the classical NCT pathway in senescent cells has been reported. However, whether this is a hallmark that exists across all types of cellular senescence remains unknown, and whether the mRNA export machinery is altered during senescence has not been demonstrated. Here, we show that the global transcriptomic downregulation of both the TREX (transcription-export) machinery and classical NLS-dependent protein transport machinery is a hallmark of varying types of senescence. A gene set-based approach using 25 different studies showed that the TREX-NCT gene set displays distinct common downregulated patterns in senescent cells versus its expression in their nonsenescent counterparts regardless of the senescence type, such as replicative senescence (RS), tumor cell senescence (TCS), oncogene-induced senescence (OIS), stem cell senescence (SCS), progeria and endothelial cell senescence (ECS). Similar patterns of TREX-NCT gene downregulation were also shown in two large human tissue genomic databases, the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. We also found that early-stage cancer tissues show consistent age-related patterns of TREX-NCT enrichment, suggesting the potential significance of TREX-NCT genes in determining cell fate in the early stage of tumorigenesis. Moreover, human cancer tissues exhibit an opposite TREX-NCT enrichment pattern with aging, indicating that deviation from age-related changes in TREX-NCT genes may provide a novel but critical clue for the age-dependent pathogenesis of cancer and increase in cancer incidence with aging.
Highlights
Cellular senescence is thought to be a fundamental mechanism of aging and tumor suppression characterized by permanent termination of cell proliferation, which may be induced by multiple mechanisms
This finding suggests the downregulation of TREXes and NCTFs in senescent cells compared to their counterparts, which we discovered to be a common feature in various types of senescent cells regardless of the cause for the senescence, such as cancer, stem cells, and cells carrying a single-gene mutation
When we applied the subclasses of the NCTFs separately, a clear enrichment pattern was observed for all three subclasses, which was most pronounced for the NPCs (Fig. 1c, f)
Summary
Cellular senescence is thought to be a fundamental mechanism of aging and tumor suppression characterized by permanent termination of cell proliferation, which may be induced by multiple mechanisms. NXF1 and NXT1, known as TREX-associated factors (TREX-AFs), are cellular mRNA transporter proteins that cooperate with TREX to facilitate nuclear export. Extensive investigation has been performed on another complex called transcription and export complex 2 (TREX-2), which is suggested to interact with NXF1 and to shuttle between transcription sites and NPC1. All these components, TREX, TREX-AFs, and TREX-2 (which we refer to as ‘TREXes’ in this paper), play a crucial role in mRNA export and ‘gene gating’, which links active gene transcription with the export of mRNA TREX, TREX-AFs, and TREX-2 (which we refer to as ‘TREXes’ in this paper), play a crucial role in mRNA export and ‘gene gating’, which links active gene transcription with the export of mRNA (see refs. 2,3 for a recent review)
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