The emerging role of alternative splicing in senescence and aging

Abstract

Deregulation of precursor mRNA splicing is associated with many illnesses and has been linked to age-related chronic diseases. Here we review recent progress documenting how defects in the machinery that performs intron removal and controls splice site selection contribute to cellular senescence and organismal aging. We discuss the functional association linking p53, IGF-1, SIRT1, and ING-1 splice variants with senescence and aging, and review a selection of splicing defects occurring in accelerated aging (progeria), vascular aging, and Alzheimer's disease. Overall, it is becoming increasingly clear that changes in the activity of splicing factors and in the production of key splice variants can impact cellular senescence and the aging phenotype.

Keywords: RNA; RNA binding proteins; aging; alternative splicing; pre-mRNA; senescence; splice variants; splicing.

Figure 1

Senescence leads to organ degeneration. The constant exposure of cells to intrinsic or extrinsic stresses may lead to senescence or apoptosis. Senescence‐associated secretory phenotypes (SASP) trigger paracrine senescence in neighboring areas to enhance senescence in tissues. When an aging immune system fails to clear senescent cells, they accumulate in tissues over time, ultimately leading to organ dysfunction.

Figure 2

Constitutive and alternative splicing. (a) The U1 snRNP recognizes the 5′ splice site on the pre‐mRNA, while U2 snRNP interacts with the branchsite near the 3′ splice site. The U4/U5/U6 tri‐snRNP complex is then recruited. After the release of U1 and U4, the spliceosome first executes 5′ splice site cleavage coupled with branch formation. The second step (3′ splice site cleavage and exon ligation) then occurs, producing the mRNA and the excised intron. (b) Alternative splicing differentially combines exons or portions thereof to increase transcriptome diversity. In the case of exon skipping, the splice sites flanking the exon are not recognized leading it to be considered as part of an intron. Different modes of alternative splicing exist. From top to bottom: constitutive splicing, exon skipping, alternative 5′ splice site use, alternative 3′ splice site use, mutually exclusive exon inclusion, and intron retention.

Figure 3

Control of alternative splicing. Exonic (ESS and ESE) and intronic (ISS and ISE) elements recruit RNA binding proteins (RBPs) to silence or enhance the use of splice sites. Interactions between RNA binding proteins may also reconfigure the architecture of the pre‐mRNA to affect splice site selection (Martinez‐Contreras et al., 2007). In addition, pre‐mRNA secondary structure may be inhibitory or may be used to approximate a regulatory element near a target splice site. Splice site selection can also be influenced by transcription. The speed of transcription will determine the time given for a complex to be assembled and influence selection when splice sites are in competition. In other cases, splicing regulators may be interacting with the polymerase complex or with chromatin to be deposited on the pre‐mRNA that emerges from the transcription complex. The presence of specific modifications on histones will impact the speed of transcription and the recruitment of adapters that in turn interact with splicing regulators.

Figure 4

p53 splice variants and aging. (a) p53 alternative splicing and the production of splice variants. The structure of the p53 gene is illustrated with exons and introns, alternative start sites of transcription (P1 and P2 arrows), and translation initiation codons (ATG). p44 is produced when intron i2 is retained, eliciting the use of a downstream initiation codon in exon 4. The use of the alternative start site (P2) leads to the production of the Δ133p53 isoform. Complex alternative splicing can occur within intron 9 to produce β or γ (α is indicated here as the simplest case where the whole intron i9 is removed). Both p44 and Δ133p53 lack the transactivation domain. (b) p44 forms a complex with p53 to regulate its activity. When overexpressed, p44 leads to senescence and hyperactivates the IGF‐1 pathway that in turn promotes cell‐cycle arrest through the RAF‐MEK‐ERK pathway. p44 is also linked to age‐related cognitive decline as its overexpression upregulates tau kinases. Variants p53β and Δ133p53 also regulate senescence by, respectively, activating and inhibiting the cell‐cycle arresting protein p21.

Figure 5

Regulating the alternative splicing of SIRT1. Skipping of exon 8 in the SIRT1 pre‐mRNA generates SIRT1Δ8. The HuR splicing factor enforces the production of SIRT1Δ8, while TIA1 and p53 (by an unknown mechanism) show the opposite effect. However, the upregulation of SIRT1Δ8 inhibits p53 leading to reciprocal regulation and a negative feedback loop.

Figure 6

ING1 splice variants and senescence. ING1 pre‐mRNA alternative splicing generates two variants termed ING1b and ING1a. In young cultured cells, ING1b is predominant and, when overexpressed, can trigger apoptosis through p53 acetylation. ING1a production increases when cells approach senescence in culture. ING1a elicits several senescence phenotypes when ectopically overexpressed.

Figure 7

The alternative splicing of LMNA produces the progerin variant that is associated with aging and age‐related diseases. The use of an alternative 5′ splice site in exon 11 of the LMNA pre‐mRNA produces a truncated mRNA variant encoding progerin. In the primary form of progeria, a silent C to T mutation in exon 11 increases the use of this cryptic site by 50‐fold. Ectopic expression of progerin causes senescence, telomere aggregation, and a progeroid phenotype in animal models. The expression of progerin can also be triggered by UVA, telomere attrition, overexpression of SRSF1, or the depletion of SRSF6.

Figure 8

Contribution of SR proteins to senescence and the aging phenotype. As indicated, SRSF1, SRSF2, SRSF3, and SRSF6 enhance or repress the production of specific splice variants implicated in age‐related phenotype, aging, and senescence.

Figure 9

A model that links telomere function with splicing control. Telomere erosion would abrogate TPE‐OLD to alter the expression/activity of splicing regulators such as SRSF2, in turn promoting a cascade of splicing alterations to affect the maintenance of genomic, chromatin, and telomere integrity (see text for details).