Structure of active human telomerase with telomere shelterin protein TPP1

Liu, Baocheng; He, Yao; Wang, Yaqiang; He, Song; Zh, Zhou; Feigon, Juli

doi:10.1038/s41586-022-04582-8

Cited by 51 publications

(71 citation statements)

References 72 publications

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“…These studies are consistent with our results. Liu et al reported that the telomere shelterin protein TPP1 can activate telomerase for telomere repeat synthesis (52). C11orf54 was found to be downregulated in clear cell renal cell carcinoma and might be a potential biomarker for the diagnosis of clear cell renal cell carcinoma (53).…”

Section: Discussionmentioning

confidence: 99%

Computational Recognition of a Regulatory T-cell-specific Signature With Potential Implications in Prognosis, Immunotherapy, and Therapeutic Resistance of Prostate Cancer

Fan

Zou

et al. 2022

Front. Immunol.

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Prostate cancer, recognized as a “cold” tumor, has an immunosuppressive microenvironment in which regulatory T cells (Tregs) usually play a major role. Therefore, identifying a prognostic signature of Tregs has promising benefits of improving survival of prostate cancer patients. However, the traditional methods of Treg quantification usually suffer from bias and variability. Transcriptional characteristics have recently been found to have a predictive power for the infiltration of Tregs. Thus, a novel machine learning-based computational framework has been presented using Tregs and 19 other immune cell types using 42 purified immune cell datasets from GEO to identify Treg-specific mRNAs, and a prognostic signature of Tregs (named “TILTregSig”) consisting of five mRNAs (SOCS2, EGR1, RRM2, TPP1, and C11orf54) was developed and validated to monitor the prognosis of prostate cancer using the TCGA and ICGC datasets. The TILTregSig showed a stronger predictive power for tumor immunity compared with tumor mutation burden and glycolytic activity, which have been reported as immune predictors. Further analyses indicate that the TILTregSig might influence tumor immunity mainly by mediating tumor-infiltrating Tregs and could be a powerful predictor for Tregs in prostate cancer. Moreover, the TILTregSig showed a promising potential for predicting cancer immunotherapy (CIT) response in five CIT response datasets and therapeutic resistance in the GSCALite dataset in multiple cancers. Our TILTregSig derived from PBMCs makes it possible to achieve a straightforward, noninvasive, and inexpensive detection assay for prostate cancer compared with the current histopathological examination that requires invasive tissue puncture, which lays the foundation for the future development of a panel of different molecules in peripheral blood comprising a biomarker of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Computational Recognition of a Regulatory T-cell-specific Signature With Potential Implications in Prognosis, Immunotherapy, and Therapeutic Resistance of Prostate Cancer

Fan

Zou

et al. 2022

Front. Immunol.

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“…Patients with solid malignancies received immune checkpoint inhibitors revealed a link between peripheral leukocyte telomere shortening and poor survival [ 55 ] . Mammalian telomeres are protected by Shelterin, a protein complex composed of six proteins including TERF telomeric repeat binding factor 1 (TRF1) [ 56 ] , TERF telomeric repeat binding factor 2 (TRF2) [ 57 ] , telomeric repeat-binding factor 2-interacting protein 1 [TERF2IP, or repressor/activator protein 1 (RAP1)] [ 58 ] , the protection of telomeres 1 (POT1) [ 59 ] , TPP1 [ 60 ] , and TRF1-interacting nuclear factor 2 (TIN2) [ 61 , 62 ] . Structure and biological function of these six Shelterin proteins have been extensively reviewed elsewhere [ 61 – 68 ] .…”

Section: Telomere Shortening and Dysfunction In Cancer Survivorsmentioning

confidence: 99%

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

Banerjee¹,

Olmsted-Davis²,

Deswal³

et al. 2022

J Cardiovasc Aging

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Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD+ depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.

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“…Conversely, what are the prospects for telomerase inhibition as a viable treatment for cancer? The crystal structure of TERT shows that the enzyme has a catalytic core that is similar to HIV and should, in principle, be druggable [187][188][189][190][191]. Aside from the usual issues of bioavailability and toxicity, there are at least two challenges that arise with the clinical use of a telomerase inhibitor.…”

Section: Therapeutic Challenges To Modulation Of Telomerase Activitymentioning

confidence: 99%

Tieing together loose ends: telomere instability in cancer and aging

2022

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Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re‐addition of G‐rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.

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Structure of active human telomerase with telomere shelterin protein TPP1

Cited by 51 publications

References 72 publications

Computational Recognition of a Regulatory T-cell-specific Signature With Potential Implications in Prognosis, Immunotherapy, and Therapeutic Resistance of Prostate Cancer

Computational Recognition of a Regulatory T-cell-specific Signature With Potential Implications in Prognosis, Immunotherapy, and Therapeutic Resistance of Prostate Cancer

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

Tieing together loose ends: telomere instability in cancer and aging

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