2021
DOI: 10.3390/cells10071616
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Abstract: Cockayne syndrome (CS) is a developmental disorder with symptoms that are typical for the aging body, including subcutaneous fat loss, alopecia, and cataracts. Here, we show that in the cells of CS patients, RNA polymerase I transcription and the processing of the pre-rRNA are disturbed, leading to an accumulation of the 18S-E intermediate. The mature 18S rRNA level is reduced, and isolated ribosomes lack specific ribosomal proteins of the small 40S subunit. Ribosomal proteins are susceptible to unfolding and … Show more

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Cited by 14 publications
(25 citation statements)
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References 37 publications
(61 reference statements)
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“…The increase of the 18S-E rRNA precursor in the XPCS1RO-SV cell line is also remarkable, as it has been recently observed in cell lines with mutated CSA and CSB protein [22]. This precursor is cleaved at site 3 to form the mature 18S.…”
Section: Plos Onesupporting
confidence: 56%
See 1 more Smart Citation
“…The increase of the 18S-E rRNA precursor in the XPCS1RO-SV cell line is also remarkable, as it has been recently observed in cell lines with mutated CSA and CSB protein [22]. This precursor is cleaved at site 3 to form the mature 18S.…”
Section: Plos Onesupporting
confidence: 56%
“…A ribosome is made of two subunits: the large subunit (LSU), constituted by the 5S, 5.8S and 28S rRNAs associated with 49 riboproteins, and the small one (SSU), constituted by the 18S rRNAs associated with 33 riboproteins [20]. Furthermore, the deregulation of the transcriptional activity of RNAP1 has previously been linked with neurodegenerative symptoms [21] and ribosome biogenesis has recently been shown to be impaired in cells expressing mutated CSA and CSB proteins [22], hinting at the importance of ribosome biogenesis in the CS phenotype.…”
Section: Introductionmentioning
confidence: 99%
“…In the mass spectrometry analysis of CSA-interacting proteins we found four ribosomal proteins of the small 40S ribosome subunits (RPS10, RPS15, RPS28 and RPSA, see Supplementary Table S8 ), which are known to enter the nucleolus in order to assemble with the ribosomal RNA (rRNA). The ability of CSA to bind ribosomal proteins has also been recently reported ( 35 ). Thus, we investigated whether FECH also interacts with the other nucleolar CSA-binding proteins.…”
Section: Resultsmentioning
confidence: 83%
“…Norther blot was performed according to previously described protocols ( 35 , 58 ). Briefly, 5 μg of total RNA was denatured at 65°C for 15 min, placed on ice for 5 min and run on a 0.9% agarose gel for 3 h at 80 V. RNAs were then transferred to Amersham Hybond membrane overnight, crosslinked with 1200 J UV and pre-hybridized for 2 h at 65°C with pre-hybridization buffer (50% formamide, 0.1% SDS, 8× Denhardt's solution, 5× SSC buffer, 50 mM NaP buffer, 0.5 mg/ml t-RNA).…”
Section: Methodsmentioning
confidence: 99%
“…The notion that ribosomal impairment may be a driver for the aging processes dates back to the 1960s, when it was proposed that errors in the translation process would be worsened if accompanied by ribosomal proteins impairment ( Orgel, 1963 ), and it took the name of “error catastrophe theory of aging” ( Gallant et al, 1997 ). Inspired by this original hypothesis, a novel pathomechanism has been proposed recently in CS cells, in which an abnormal RNA polymerase I (RNA pol I) transcription activity was shown to affect ribosomal performance, inducing both misfolded proteins ( Alupei et al, 2018 ; Qiang et al, 2021 ) and nucleolar stress, with the latter characterized by a p53-regulated cell cycle arrest and senescence and/or apoptosis. The decreased RNA pol I transcription is followed by ribosomal malfunction, loss of proteostasis, and Endoplasmic reticulum (ER) stress-induced inhibition of rRNA synthesis all of which lead to death of CS cells.…”
Section: The Unbalance Of Cs Proteins In Aging and Cancermentioning
confidence: 99%