RT Journal Article
SR Electronic
T1 Reduced RNA turnover as a driver of cellular senescence
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000809
DO 10.26508/lsa.202000809
VO 4
IS 3
A1 Nowsheen Mullani
A1 Yevheniia Porozhan
A1 Adèle Mangelinck
A1 Christophe Rachez
A1 Mickael Costallat
A1 Eric Batsché
A1 Michele Goodhardt
A1 Giovanni Cenci
A1 Carl Mann
A1 Christian Muchardt
YR 2021
UL https://www.life-science-alliance.org/content/4/3/e202000809.abstract
AB 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.