Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Dec 23

PMID 38137431

Authors

Paola Canale

Jonica Campolo

Andrea Borghini

Maria Grazia Andreassi

Affiliations

Soon will be listed here.

Abstract

Telomere dysfunction is implicated in vascular aging and shorter leucocyte telomeres are associated with an increased risk of atherosclerosis, myocardial infarction, and heart failure. Another pathophysiological mechanism that explains the causal relationship between telomere shortening and atherosclerosis development focuses on the clonal hematopoiesis of indeterminate potential (CHIP), which represents a new and independent risk factor in atherosclerotic cardiovascular diseases. Since telomere attrition has a central role in driving vascular senescence, understanding telomere biology is essential to modulate the deleterious consequences of vascular aging and its cardiovascular disease-related manifestations. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for "TElomeric Repeat-containing RNA", actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the multiple biological functions of TERRA remain to be largely elucidated. In particular, the role of TERRA in vascular biology is surprisingly unknown. In this review, we discuss the current knowledge of TERRA and its roles in telomere biology. Additionally, we outline the pieces of evidence that exist regarding the relationship between TERRA dysregulation and disease. Finally, we speculate on how a comprehensive understanding of TERRA transcription in the cardiovascular system may provide valuable insights into telomere-associated vascular aging, offering great potential for new therapeutic approaches.

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References

Huang Y, Wang C . Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease. Int J Mol Sci. 2021; 22(18). PMC: 8467562. DOI: 10.3390/ijms22189867. View

Rippe K, Luke B . TERRA and the state of the telomere. Nat Struct Mol Biol. 2015; 22(11):853-8. DOI: 10.1038/nsmb.3078. View

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

Hamczyk M, Nevado R, Barettino A, Fuster V, Andres V . Biological Versus Chronological Aging: JACC Focus Seminar. J Am Coll Cardiol. 2020; 75(8):919-930. DOI: 10.1016/j.jacc.2019.11.062. View

Gao Y, Zhang J, Liu Y, Zhang S, Wang Y, Liu B . Regulation of TERRA on telomeric and mitochondrial functions in IPF pathogenesis. BMC Pulm Med. 2017; 17(1):163. PMC: 5712138. DOI: 10.1186/s12890-017-0516-1. View

Chang K, Chen Y, Wu W, Shen H, Huang K, Chu H . Expression of Telomeric Repeat-Containing RNA Decreases in Sarcopenia and Increases after Exercise and Nutrition Intervention. Nutrients. 2020; 12(12). PMC: 7762552. DOI: 10.3390/nu12123766. View

Tall A, Fuster J . Clonal hematopoiesis in cardiovascular disease and therapeutic implications. Nat Cardiovasc Res. 2022; 1(2):116-124. PMC: 9631799. DOI: 10.1038/s44161-021-00015-3. View

Yegorov Y, Poznyak A, Nikiforov N, Starodubova A, Orekhov A . Role of Telomeres Shortening in Atherogenesis: An Overview. Cells. 2021; 10(2). PMC: 7918954. DOI: 10.3390/cells10020395. View

Rivosecchi J, Cusanelli E . TERRA beyond cancer: the biology of telomeric repeat-containing RNAs in somatic and germ cells. Front Aging. 2023; 4:1224225. PMC: 10448526. DOI: 10.3389/fragi.2023.1224225. View

10.

Haycock P, Heydon E, Kaptoge S, Butterworth A, Thompson A, Willeit P . Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2014; 349:g4227. PMC: 4086028. DOI: 10.1136/bmj.g4227. View

11.

Feretzaki M, Lingner J . A practical qPCR approach to detect TERRA, the elusive telomeric repeat-containing RNA. Methods. 2016; 114:39-45. DOI: 10.1016/j.ymeth.2016.08.004. View

12.

Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman P . TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell. 2009; 35(4):403-13. PMC: 2749977. DOI: 10.1016/j.molcel.2009.06.025. View

13.

Aguado J, Sola-Carvajal A, Cancila V, Revechon G, Ong P, Jones-Weinert C . Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome. Nat Commun. 2019; 10(1):4990. PMC: 6861280. DOI: 10.1038/s41467-019-13018-3. View

14.

Ungvari Z, Tarantini S, Sorond F, Merkely B, Csiszar A . Mechanisms of Vascular Aging, A Geroscience Perspective: JACC Focus Seminar. J Am Coll Cardiol. 2020; 75(8):931-941. PMC: 8559983. DOI: 10.1016/j.jacc.2019.11.061. View

15.

Yeh J, Lin M, Wang C . Telomeres as Therapeutic Targets in Heart Disease. JACC Basic Transl Sci. 2020; 4(7):855-865. PMC: 6978555. DOI: 10.1016/j.jacbts.2019.05.009. View

16.

Suda M, Paul K, Minamino T, Miller J, Lerman A, Ellison-Hughes G . Senescent Cells: A Therapeutic Target in Cardiovascular Diseases. Cells. 2023; 12(9). PMC: 10177324. DOI: 10.3390/cells12091296. View

17.

Diman A, Boros J, Poulain F, Rodriguez J, Purnelle M, Episkopou H . Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription. Sci Adv. 2016; 2(7):e1600031. PMC: 5087959. DOI: 10.1126/sciadv.1600031. View

18.

Scionti F, Juli G, Rocca R, Polera N, Nadai M, Grillone K . TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma. J Exp Clin Cancer Res. 2023; 42(1):71. PMC: 10041726. DOI: 10.1186/s13046-023-02633-0. View

19.

Schoeftner S, Blasco M . Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol. 2007; 10(2):228-36. DOI: 10.1038/ncb1685. View

20.

Noothi S, Ahmed M, Agrawal D . Residual risks and evolving atherosclerotic plaques. Mol Cell Biochem. 2023; 478(12):2629-2643. PMC: 10627922. DOI: 10.1007/s11010-023-04689-0. View