Reduced RNA turnover as a driver of cellular senescence

Abstract

Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. The inflammatory phenotype of senescent cells was previously shown to be driven by cytoplasmic DNA. Here, we propose that cytoplasmic double-stranded RNA has a similar effect. We find that several cell types driven into senescence by different routes share an accumulation of long promoter RNAs and 3′ gene extensions rich in retrotransposon sequences. Accordingly, these cells display increased expression of genes involved in response to double stranded RNA of viral origin downstream of the interferon pathway. The RNA accumulation is associated with evidence of reduced RNA turnover, including in some cases, reduced expression of RNA exosome subunits. Reciprocally, depletion of RNA exosome subunit EXOSC3 accelerated expression of multiple senescence markers. A senescence-like RNA accumulation was also observed in cells exposed to oxidative stress, an important trigger of cellular senescence. Altogether, we propose that in a subset of senescent cells, repeat-containing transcripts stabilized by oxidative stress or reduced RNA exosome activity participate in driving and maintaining the permanent inflammatory state characterizing cellular senescence.

Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function

“…This phenotype appears to be associated with reduced expression of RNA exosome subunits, such as DIS3L (the catalytic subunit of the cytoplasmic RNA exosome complex), EXOSC3, and EXOSC9, in several cell types. Consistently, depletion of EXOSC3 accelerated expression of multiple senescence markers and induced a senescent-like phenotype [82].…”

“…In addition, a recent report has shown that the RNA exosome-mediated RNA turnover has an important role in cellular senescence [82]. Senescent cells exhibit reduced turnover of multiple unstable RNAs, including 3 extended U snRNAs and uaRNAs, short-lived mRNAs, and upregulation of the interferon-inducible genes [82].…”

“…In addition, a recent report has shown that the RNA exosome-mediated RNA turnover has an important role in cellular senescence [82]. Senescent cells exhibit reduced turnover of multiple unstable RNAs, including 3 extended U snRNAs and uaRNAs, short-lived mRNAs, and upregulation of the interferon-inducible genes [82]. This phenotype appears to be associated with reduced expression of RNA exosome subunits, such as DIS3L (the catalytic subunit of the cytoplasmic RNA exosome complex), EXOSC3, and EXOSC9, in several cell types.…”

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

“…4F ). Both OAS1 and OAS3 genes encode enzymes which activate ribonuclease L to degrade intracellular double-stranded RNA as part of the antiviral response (Choi et al 2015) and cellular homeostasis (Mullani et al 2021).…”

“…We engineered Calu-3 cells to reduce expression of EXOSC2 and demonstrated a significant suppression of SARS-CoV-2 replication. Transcriptome analysis revealed that reduced expression of EXOSC2 leads to an upregulation of OAS gene expression which is independent of infection or inflammation, possibly as part of a homeostatic response (Mullani et al 2021). OAS proteins are key mediators of viral RNA degradation (Choi et al 2015) and have been linked to a successful immune response against SARS-CoV-2 (Huffman et al 2022; Wickenhagen et al 2021); it is likely that OAS protein upregulation is one reason for the negative effect of reduced EXOSC2 on SARS-CoV-2 replication.…”