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

Abstract

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.

Novel Diazirine‐Containing DNA Photoaffinity Probes for the Investigation of DNA‐Protein‐Interactions

“…Interestingly, mouse models of ATR deficiency either with alleles found in human patients43 or with a conditional knockout allele to avoid embryonic lethality seen in full knockouts44 show premature aging. Although ATR is a kinase associated with DNA damage repair processes, the protein is also implicated in RNA metabolism, specifically in splicing of transcription initiation factor TFIID subunit 1 (TAF1), a subunit of RNA polymerase 45–47. Therefore, it seems reasonable to infer that ATR mutations affect RNA metabolism by a slightly indirect mechanism.…”

Interferon-gamma enhances radiation-induced cell death via downregulation of Chk1

“…ATR, a kinase upstream of Chk1, was phosphorylated at serine 428 whereas Chk1 was phosphorylated at serine 345 after a 12 h IFNγ treatment. Since the phosphorylation sites are associated with activation of the kinases, 21,22 ATR-Chk1 signaling might be associated with IFNγ-induced responses. Phosphorylation of both ATR and Chk1 increased in the presence of IFNγ in a dose-dependent manner whereas ATM phosphorylation was not increased by the conditions (Fig.…”

Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding

“… SUMMARY Defective RNA metabolism and transport are implicated in aging and degeneration[1, 2], but the underlying mechanisms remain poorly understood. A prevalent feature of aging is mitochondrial deterioration[3].…”