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A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1

ABSTRACT: A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1

PROVIDER: PRJNA674659 | ENA |

REPOSITORIES: ENA

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A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1

Project description:Telomere erosion contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide screen to identify gene deletions that sensitized p53-positive human cells to loss of telomere integrity, and uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1: TAPR1. CRISPR-Cas9 mediated deletion of TAPR1 led to elevated p53 and induction of p53 transcriptional targets. TAPR1-disrupted cells exhibited a synthetic-sick relationship with the loss of telomerase, or treatment with the topoisomerase II inhibitor doxorubicin. Stabilization of p53 with nutlin-3a further decreased cell fitness in cells lacking TAPR1 or telomerase, whereas deletion of TP53 rescued the decreased fitness of TAPR1-deleted cells. We propose that TAPR1 regulates p53 turnover, thereby tapering the p53-dependent response to telomere erosion. We discuss the possible implications of such a mechanism in the preservation of genome integrity during senescence or aging.

2021-03-04 | PXD022128 | Pride

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [TAPR1_KO]

Project description:Telomere erosion in cells with insufficient levels of the telomerase reverse transcriptase, TERT, contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide screen to identify gene deletions that sensitized p53-positive human cells to telomerase inhibition. We uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1, TAPR1, that exhibited a synthetic-sick relationship with TERT loss. A genome-wide screen in TAPR1-disrupted cells also identified TERT as a sensitizing gene deletion. Additional genetic and transcriptome analysis of TAPR1-disrupted cells revealed that TAPR1 tapered p53 activation in response to eroded telomeres, p53 stabilization with nutlin-3a, or DNA damage. Importantly, deletion of TP53 rescued the fitness defect in TAPR1-disrupted cells. These findings identify C16ORF72/TAPR1 as new regulator at the nexus between telomere integrity and p53 regulation.

2021-03-04 | GSE160867 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [BIBR_screen]

2021-03-04 | GSE160843 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [RNA-seq]

2021-03-04 | GSE160865 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [BIBR_screen]

Project description:A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [BIBR_screen]

| PRJNA674626 | ENA

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [TAPR1_KO]

Project description:A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [TAPR1_KO]

| PRJNA674661 | ENA

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [RNA-seq]

Project description:A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [RNA-seq]

| PRJNA674657 | ENA

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-03-04 | GSE160869 | GEO

Mutant telomerase RNAs induce DNA damage and apoptosis via the TRF2-ATM pathway in telomerase-overexpressing primary fibroblasts

Project description:Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancer cells with high telomerase activity. However, the mechanism by which MT-hTers inhibit growth of cancer cells and their effects on normal cells remain unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 lung fibroblasts that have low telomerase levels. Growth of IMR90 cells following MT-hTers infection was not significantly impaired; however, similar treatments in telomerase-overexpressing IMR90 (IMR90 WThTERT) cells inhibited cell proliferation and induced apoptosis. Confocal microscopy showed that MT-hTers induced DNA damage foci i.e. 53BP1 and γ-H2AX in IMR90 WThTERT cells. Microarray analysis revealed that GADD45γ was significantly elevated in MT-hTers treated IMR90 WThTERT cells. MT-hTers also induced ATM phosphorylation at Ser 1981 in IMR90 WThTERT cells, and Western blot analysis revealed high levels of phosphorylated p53 following down-regulation of cellular TRF2 expression in MT-hTers treated IMR90 WThTERT cells. Taken together, we have elucidated that MT-hTers induce double-stranded DNA breaks (DSBs)-like damages in telomerase-positive IMR90 WThTERT cells following phosphorylation of ATM and p53 via suppression of TRF2 which eventually may have led to apoptosis via elevation of GADD45γ.

2011-05-29 | GSE24975 | GEO

Expression profile of telomerase deficient iPSC

Project description:Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and causing malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of specific human diseases. We derived induced pluripotent stem cells (iPSCs) from patients with mutations in the TERT and TERC telomerase genes. Telomerase-mutant iPSCs elongated telomeres, but at a lower rate than healthy iPSCs, and the magnitude of the elongation deficit correlated with the specific mutation’s impact on telomerase activity. However, elongation significantly varied among iPSC clones harboring the same mutation, and was affected by genetic and environmental factors. iPSCs cultured in hypoxia showed increased telomere length. Potential influence of residual expression of reprogramming factors on telomerase regulation and telomere length was ruled out by excising the transgenes after successful reprogramming. Evidence for telomerase-independent telomere elongation was not observed in these cells. We demonstrate that telomerase is required for telomere elongation in iPSCs and uncover heterogeneity in telomere maintenance even between clones derived from individual patients or siblings with the same mutation, indicating that telomere phenotype may be influenced by acquired and environmental agents. Our data underscore the necessity of studying multiple clones when using iPSCs to model disease. The exon array were done to validate the pluripotent phenotype of the derived normal and telomerase mutant iPSC and to potentially identify differentially expressed genes in mutant iPSC. Objective: confirming pluripotency by comparing telomerase mutated-, control-iPSC to human ESC and to their parental somatic cells (fibroblast used for iPSC derivation) 20 samples total, 5 different fibroblast cells, 13 iPSC lines, 1 ES line (H1) from different passages

2013-02-11 | E-GEOD-42869 | biostudies-arrayexpress

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