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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160869 | GEO | 2021/03/04

REPOSITORIES: GEO

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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 novel p53 regulator, C16ORF72/TAPR1, buffers against telomerase inhibition.

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 CRISPR 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 subsequent genome-wide CRISPR screen in TAPR1-disrupted cells reciprocally identified TERT as a sensitizing gene deletion. Cells lacking TAPR1 or TERT possessed elevated p53 levels and transcriptional signatures consistent with p53 upregulation. The elevated p53 response in TERT- or TAPR1-deficient cells was exacerbated by treatment with the MDM2 inhibitor and p53 stabilizer nutlin-3a and coincided with a further reduction in cell fitness. Importantly, the sensitivity to treatment with nutlin-3a in TERT- or TAPR1-deficient cells was rescued by loss of p53. These data suggest that TAPR1 buffers against the deleterious consequences of telomere erosion or DNA damage by constraining p53. These findings identify C16ORF72/TAPR1 as new regulator at the nexus of telomere integrity and p53 regulation.

| S-EPMC8045932 | biostudies-literature

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

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

| PRJNA674659 | 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 [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 [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 yeast chemical genetic screen identifies inhibitors of human telomerase.

Project description:Telomerase comprises a reverse transcriptase and an internal RNA template that maintains telomeres in many eukaryotes, and it is a well-validated cancer target. However, there is a dearth of small molecules with efficacy against human telomerase in vivo. We developed a surrogate yeast high-throughput assay to identify human telomerase inhibitors. The reversibility of growth arrest induced by active human telomerase was assessed against a library of 678 compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds identified reproducibly restored growth to strains expressing active human telomerase, and three of these four compounds also specifically inhibited purified human telomerase in vitro. These compounds represent probes for human telomerase function, and potential entry points for development of lead compounds against telomerase-positive cancers.

| S-EPMC3650558 | biostudies-literature

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