Age-dependence of nuclear RNA processing

Yannarell, Anthony C.; Schumm, Dorothy E.; Webb, Thomas E.

doi:10.1016/0047-6374(77)90026-4

Cited by 43 publications

(20 citation statements)

References 14 publications

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“…Previously thought to be a relatively uncommon phenomenon, AS has recently been shown to be widespread throughout the genome (Modrek & Lee, 2002). Studies in rats and mice have shown that increased age is associated with changes in mRNA processing leading to aberrant splicing (Yannarell et al ., 1977; Meshorer & Soreq, 2002). Normal aging has also been found to be associated with an aberrant increase in the production and maturation of many mRNAs in human peripheral blood leukocytes (Harries et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

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SummaryAlternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome‐wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild‐type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3–3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson–Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild‐type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

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Section: Introductionmentioning

confidence: 99%

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

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“…Information however, regarding organization and distribution of the newly synthesized RNA and the pathways implicated in this process remains elusive. Reduction in the RNA synthesis and processing machinery has also been reported to accompany in vivo aging in rats (Lindholm 1986;Yannarell et al 1977). Other investigators have reported decreased transcription fidelity which may result in the insertion of false base in human fibroblasts as a function of the donor's age but also as a result of in vitro senescence (Paoloni-Giacobino et al 2001).…”

Section: Discussionmentioning

confidence: 93%

“…Increased rate of transcription errors during both in vivo and in vitro aging has been reported by other investigators (Paoloni-Giacobino et al 2001). The study of mRNA synthesis and processing during replicative senescence (Nose and Okamoto 1980) may yield significant information, directly related to in vivo aging (Lindholm 1986;Meshorer and Soreq 2002;Yannarell et al 1977) but also to a broad spectrum of human diseases (Faustino and Cooper 2003;Moraes 2009). Despite this increasing interest, information regarding the spatiotemporal regulation of the RNA processing in senescent fibroblasts and a relevant role for ATR is still missing.…”

Section: Introductionmentioning

confidence: 92%

Compromise in mRNA processing machinery in senescent human fibroblasts: implications for a novel potential role of Phospho-ATR (ser428)

et al. 2010

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Ataxia-Telangiectasia and Rad3 related kinase (ATR) is a major gatekeeper of genomic stability and has been the subject of exhaustive study in the context of cell cycle progression and senescence as a DNA damage-induced response. Conditional knockout of the kinase in adult mice results in accelerated aging phenomena, such as such hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. In addition to that, recent reports strongly implicate signaling mediated by this kinase in the regulation of alternative splicing of certain, mostly cancer-associated transcripts. Interest to the function of mRNA synthesis and processing is constantly increasing as severe degenerative diseases, such as cancer, cystic fibrosis and Hutchinson-Gilford progeria syndrome are at least partly attributed to these abnormalities. In light of the above, we investigate the RNA processing machinery in senescent fibroblasts as opposed to young, either exponentially proliferating or quiescent, further focusing on the distribution and localization of active, phosphorylated ATR at ser428. This study implicates the spatiotemporal presence of the phosphorylated kinase in the regulation of mRNA splicing and polyadenylation. This function appears perturbed in senescent cells, accompanied by a distinct pattern of phospho-ATR in the senescent nucleus.

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“…The sedimentation coefficient of the preparation was 11. 7 The poly(A)-RNP, complex between poly(A) and poly(A)-associated proteins, was obtained after binding of polysomal mRNA to oligo(dT)-cellulose and subsequent digestion with RNase A and RNase T I [29]. The poly(A)-RNP fraction was obtained by elution with low salt (25 mM Tris/HCl, pH 8.0; 2.5 mM MgC12) from oligo(dT)-cellulose.…”

Section: R N a Preparationsmentioning

confidence: 99%

“…The latter function might be concluded from observations which revealed that in reconstituted cell-free systems rapidly labeled RNA is released from nuclei, but rRNA is not [6]. 65 "/, of this rapidly labeled RNA has been determined to be polyadenylated [7]. The release of RNA in vitro is dependent upon the presence of ATP [8], suggesting that an adenosine triphosphatase is involved in mRNA transport through nuclear pores.…”

mentioning

confidence: 99%

Modulation of the Nuclear‐Envelope Nucleoside Triphosphatase by Poly(A)‐rich mRNA and by Microtubule Protein

Bernd

Schröder

Ζahn

et al. 1982

European Journal of Biochemistry

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Nuclear envelopes contain a nucleoside triphosphatase which is thought to be involved in the supply of energy for nucleo-cytoplasmic RNA transport. This enzyme is stimulated most efficiently by poly(A) and to a lesser extent by poly(G) and poly(dT). Half-maximal stimulation of the enzyme from rat liver nuclei, which was associated with the poly(A)-specific endoribonuclease IV and was free from poly(A) polymerase and endoribonuclease V activity, was determined to occur at a concentration of 1.1 x lo6 poly(A) molecules/nuclear ghost. Double-reciprocal plot analyses revealed a 2.8-fold stimulation of the enzyme by poly(A). Poly(A) in the hybrid form had no influence on the activity of the nucleoside triphosphatase. Stimulation by oligo(A) required a minimum chain length of 18 nucleotide units. Naturally occurring R N A species enhanced the nucleoside triphosphatase activity, provided that they contained a poly(A) segment. Using poly(A)-rich mRNA, half-maximal stimulation was determined to proceed at 0.5 x 106 niolecules/nuclear ghost. Removal of the poly(A) segment from mRNA abolished the stimulatory effect on the enzyme.Microtubule protein was found to inhibit the nucleoside triphosphatase efficiently. At a concentration of 2.0 mg/ml, polymerized microtubule protein reduced the enzyme activity by 96 %. Dimeric tubulin was less inhibitory, while actin was without any significant effect. From these findings it is suggested that a possible nucleoside-triphosphatase-mediated transport of poly(A)-rich mRNA through nuclear envelopes is controlled, first, by the poly(A) segment of this R N A species and, secondly, by cytoplasmic microtubules.Eukaryotic messenger RNA (mRNA) derives from precursors which have been termed heterogeneous nuclear R N A (hnRNA). This conversion involves two well-defined steps during which nucleic acid is synthesized by template-independent enzyme reactions, the addition of poly(A) [l] and 5'-cap formation [2]. Recent studies suggest that poly(A) tracts are involved in gene splicing [3], stabilization of mRNA [4], formation of the termination codon for translation [5] and perhaps in transport of mRNA through nuclear pores. The latter function might be concluded from observations which revealed that in reconstituted cell-free systems rapidly labeled RNA is released from nuclei, but rRNA is not [6]. 65 "/, of this rapidly labeled RNA has been determined to be polyadenylated [7]. The release of RNA in vitro is dependent upon the presence of ATP [8], suggesting that an adenosine triphosphatase is involved in mRNA transport through nuclear pores. Therefore, interest has focused on the nuclear-membrane-bound, Mg2+-dependent nucleoside triphosphatase [%Ill.

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Age-dependence of nuclear RNA processing

Cited by 43 publications

References 14 publications

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Compromise in mRNA processing machinery in senescent human fibroblasts: implications for a novel potential role of Phospho-ATR (ser428)

Modulation of the Nuclear‐Envelope Nucleoside Triphosphatase by Poly(A)‐rich mRNA and by Microtubule Protein

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