Emerging Mechanisms of Telomerase Reactivation in Cancer

Overview

Journal Trends Cancer

Publisher Cell Press

Specialty Oncology

Date 2022 May 14

PMID 35568649

Authors

Shalu Sharma

Shantanu Chowdhury

Affiliations

Soon will be listed here.

Abstract

Mutations in the promoter of human telomerase reverse transcriptase (hTERT) result in hyperactivation of hTERT. Notably, all mutations are G>A transitions, frequently found in a wide range of cancer types, and causally associated with cancer progression. Initially, the mutations were understood to reactivate hTERT by generating novel E26 transformation-specific (ETS) binding sites. Recent work reveals the role of DNA secondary structure G-quadruplexes, telomere binding factor(s), and chromatin looping in hTERT regulation. Here, we discuss these emerging findings in relation to the clinically significant promoter mutations to provide a broader understanding of the context-dependent outcomes that result in hTERT activation in normal and pathogenic conditions.

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References

Jang J, Kim J, Kim H, Tak K, Lee S, Nam H . Significance of Genetic Alterations and Telomere Length in Hepatocellular Carcinoma. Cancers (Basel). 2021; 13(9). PMC: 8125722. DOI: 10.3390/cancers13092160. View

Sengupta A, Roy S, Chowdhury S . Non-duplex G-Quadruplex DNA Structure: A Developing Story from Predicted Sequences to DNA Structure-Dependent Epigenetics and Beyond. Acc Chem Res. 2020; 54(1):46-56. PMC: 7612685. DOI: 10.1021/acs.accounts.0c00431. View

Dubbink H, Bakels H, Post E, Zwarthoff E, Verdijk R . TERT promoter mutations and BRAF mutations are rare in sporadic, and TERT promoter mutations are absent in NF1-related malignant peripheral nerve sheath tumors. J Neurooncol. 2014; 120(2):267-72. DOI: 10.1007/s11060-014-1553-8. View

Kotla S, Vu H, Ko K, Wang Y, Imanishi M, Heo K . Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein. JCI Insight. 2019; 4(9). PMC: 6538340. DOI: 10.1172/jci.insight.124867. View

Xu X, Li Y, Bharath S, Ozturk M, Bowler M, Loo B . Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1. Nat Commun. 2018; 9(1):3183. PMC: 6085347. DOI: 10.1038/s41467-018-05644-0. View

Duronio R, Xiong Y . Signaling pathways that control cell proliferation. Cold Spring Harb Perspect Biol. 2013; 5(3):a008904. PMC: 3578363. DOI: 10.1101/cshperspect.a008904. View

Liu X, Qu S, Liu R, Sheng C, Shi X, Zhu G . TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab. 2014; 99(6):E1130-6. PMC: 4037723. DOI: 10.1210/jc.2013-4048. View

Chiba K, Johnson J, Vogan J, Wagner T, Boyle J, Hockemeyer D . Cancer-associated TERT promoter mutations abrogate telomerase silencing. Elife. 2015; 4. PMC: 4507476. DOI: 10.7554/eLife.07918. View

Huang F, Hodis E, Xu M, Kryukov G, Chin L, Garraway L . Highly recurrent TERT promoter mutations in human melanoma. Science. 2013; 339(6122):957-9. PMC: 4423787. DOI: 10.1126/science.1229259. View

10.

Sahm F, Schrimpf D, Olar A, Koelsche C, Reuss D, Bissel J . TERT Promoter Mutations and Risk of Recurrence in Meningioma. J Natl Cancer Inst. 2015; 108(5). PMC: 4849806. DOI: 10.1093/jnci/djv377. View

11.

Akincilar S, Chan C, Ng Q, Fidan K, Tergaonkar V . Non-canonical roles of canonical telomere binding proteins in cancers. Cell Mol Life Sci. 2021; 78(9):4235-4257. PMC: 8164586. DOI: 10.1007/s00018-021-03783-0. View

12.

Mukherjee A, Sharma S, Sengupta S, Saha D, Kumar P, Hussain T . Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends. PLoS Genet. 2018; 14(11):e1007782. PMC: 6264879. DOI: 10.1371/journal.pgen.1007782. View

13.

Lee S, Barnhill R, Dummer R, Dalton J, Wu J, Pappo A . TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. Sci Rep. 2015; 5:11200. PMC: 4462090. DOI: 10.1038/srep11200. View

14.

Teo H, Ghosh S, Luesch H, Ghosh A, Wong E, Malik N . Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression. Nat Cell Biol. 2010; 12(8):758-67. DOI: 10.1038/ncb2080. View

15.

Shanmugam R, Ozturk M, Low J, Akincilar S, Chua J, Thangavelu M . Genome-wide screens identify specific drivers of mutant promoters. Proc Natl Acad Sci U S A. 2022; 119(3). PMC: 8784157. DOI: 10.1073/pnas.2105171119. View

16.

Barczak W, Suchorska W, Sobecka A, Bednarowicz K, Machczynski P, Golusinski P . hTERT C250T promoter mutation and telomere length as a molecular markers of cancer progression in patients with head and neck cancer. Mol Med Rep. 2017; 16(1):441-446. DOI: 10.3892/mmr.2017.6590. View

17.

Ding D, Xi P, Zhou J, Wang M, Cong Y . Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NF-κB-dependent transcription. FASEB J. 2013; 27(11):4375-83. DOI: 10.1096/fj.13-230904. View

18.

Wang Z, Deng Z, Dahmane N, Tsai K, Wang P, Williams D . Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes. Proc Natl Acad Sci U S A. 2015; 112(46):E6293-300. PMC: 4655533. DOI: 10.1073/pnas.1505962112. View

19.

Horikawa I, Cable P, Afshari C, Barrett J . Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res. 1999; 59(4):826-30. View

20.

Miglietta G, Russo M, Capranico G . Correction to article 'G-quadruplex-R-loop interactions and the mechanism of anticancer G-quadruplex binders'. Nucleic Acids Res. 2021; 49(10):6000-6001. PMC: 8191755. DOI: 10.1093/nar/gkab483. View