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Updated: Nov 15, 2025
Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
A novel p53 regulator, C16ORF72/TAPR1, buffers against telomerase inhibition
Yahya Benslimane1, María Sánchez-Osuna1, Jasmin Coulombe-Huntington1
1Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.
Abstract:
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.
Insights
Telomere erosion links to aging and cell dysfunction. Researchers discovered a new gene, TAPR1, that works with telomerase reverse transcriptase (TERT) to control the p53 protein, impacting cell health.
Area of Science:
- Cell Biology
- Genetics
- Molecular Biology
Background:
- Telomere attrition, driven by insufficient telomerase reverse transcriptase (TERT), contributes to cellular senescence and age-related tissue dysfunction.
- The tumor suppressor protein p53 is a key mediator of cellular responses to telomere damage.
Purpose of the Study:
- To identify genes that, when deleted, sensitize p53-positive human cells to telomerase inhibition.
- To elucidate the relationship between telomere maintenance, p53 regulation, and cellular response to stress.
Main Methods:
- Genome-wide CRISPR screens were employed to identify sensitizing gene deletions.
- Functional assays were performed on cells with disrupted TERT or the novel gene C16ORF72 (TAPR1).
- The effects of MDM2 inhibition (nutlin-3a) on cell fitness were assessed in various genetic backgrounds.
Main Results:
- A previously unannotated gene, C16ORF72 (named TAPR1), was identified with a synthetic-sick interaction with TERT loss.
- Disruption of TAPR1 or TERT led to elevated p53 levels and increased sensitivity to p53 stabilization with nutlin-3a.
- Loss of p53 rescued the sensitivity of TERT- or TAPR1-deficient cells to nutlin-3a, indicating p53's central role.
Conclusions:
- TAPR1 acts as a novel regulator that constrains p53 activity, buffering against telomere erosion and DNA damage.
- C16ORF72/TAPR1 functions at the critical intersection of telomere integrity and p53 pathway regulation.
- These findings reveal a new mechanism controlling cellular responses to telomere dysfunction and DNA damage.
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