Decoding Telomere Protein Rap1: Its Telomeric and Nontelomeric Functions and Potential Implications in Diabetic Cardiomyopathy

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2017 Aug 31

PMID 28853973

Citations 27

Authors

Yin Cai

Vidya Kandula

Ramoji Kosuru

Xiaodong Ye

Michael G Irwin

Zhengyuan Xia

Affiliations

Soon will be listed here.

Abstract

Mammalian Rap1, the most conserved telomere-interacting protein, beyond its role within nucleus for the maintenance of telomeric functions, is also well known for its pleiotropic functions in various physiological and pathological conditions associated with metabolism, inflammation and oxidative stress. For all these, nowadays Rap1 is the subject of critical investigations aimed to unveil its molecular signaling pathways and to scrutinize the applicability of its modulation as a promising therapeutic strategy with clinical relevance. However, the underlying intimate mechanisms of Rap1 are not extensively studied, but any modulation of this protein level has been associated with pathologies like inflammation, oxidative stress and deregulated metabolism. This is considerably important in light of the recent discovery of Rap1 modulation in diseases like cancer and cardiac metabolic disorders. In this review, we focus on both the telomeric and nontelomeric functions of Rap1 and its modulation in various health risks, especially on the heart.

Citing Articles

Peptide design to control protein-protein interactions.

van Wier S, Beekman A Chem Soc Rev. 2025; 54(4):1684-1698.

PMID: 39817557 PMC: 11736853. DOI: 10.1039/d4cs00243a.

Transcriptional profiling reveals the role of Candida albicans Rap1 in oxidative stress response.

Wang W, Chen H, Chen S, Lan C Biosci Rep. 2024; 44(12).

PMID: 39575984 PMC: 11667096. DOI: 10.1042/BSR20240689.

Harnessing alkaline-pH regulatable promoters for efficient methanol-free expression of enzymes of industrial interest in Komagataella Phaffii.

Albacar M, Casamayor A, Arino J Microb Cell Fact. 2024; 23(1):99.

PMID: 38566096 PMC: 10985989. DOI: 10.1186/s12934-024-02362-9.

Unwrap RAP1's Mystery at Kinetoplastid Telomeres.

Li B Biomolecules. 2024; 14(1).

PMID: 38254667 PMC: 10813129. DOI: 10.3390/biom14010067.

Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis.

Torres-Montaner A Curr Issues Mol Biol. 2023; 45(9):7582-7616.

PMID: 37754262 PMC: 10527771. DOI: 10.3390/cimb45090478.

References

Butler G, Dawes I, McConnell D . TUF factor binds to the upstream region of the pyruvate decarboxylase structural gene (PDC1) of Saccharomyces cerevisiae. Mol Gen Genet. 1990; 223(3):449-56. DOI: 10.1007/BF00264453. View

Salpea K, Talmud P, Cooper J, Maubaret C, Stephens J, Abelak K . Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis. 2009; 209(1):42-50. PMC: 2839074. DOI: 10.1016/j.atherosclerosis.2009.09.070. View

Lu W, Zhang Y, Liu D, Songyang Z, Wan M . Telomeres-structure, function, and regulation. Exp Cell Res. 2012; 319(2):133-41. PMC: 4051234. DOI: 10.1016/j.yexcr.2012.09.005. View

Benetos A, Gardner J, Zureik M, Labat C, Xiaobin L, Adamopoulos C . Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects. Hypertension. 2004; 43(2):182-5. DOI: 10.1161/01.HYP.0000113081.42868.f4. View

Zhang B, Shen Q, Chen Y, Pan R, Kuang S, Liu G . Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy. Sci Rep. 2017; 7:44239. PMC: 5347164. DOI: 10.1038/srep44239. View

Shore D, Nasmyth K . Purification and cloning of a DNA binding protein from yeast that binds to both silencer and activator elements. Cell. 1987; 51(5):721-32. DOI: 10.1016/0092-8674(87)90095-x. View

Hegan D, Lu Y, Stachelek G, Crosby M, Bindra R, Glazer P . Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010; 107(5):2201-6. PMC: 2836641. DOI: 10.1073/pnas.0904783107. View

Armanios M . Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest. 2013; 123(3):996-1002. PMC: 3673231. DOI: 10.1172/JCI66370. View

Zhang Y, Chiu S, Liang X, Gao F, Zhang Z, Liao S . Rap1-mediated nuclear factor-kappaB (NF-κB) activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction. Cell Death Discov. 2016; 1:15007. PMC: 4981000. DOI: 10.1038/cddiscovery.2015.7. View

10.

Libby P, Ridker P, Hansson G . Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009; 54(23):2129-38. PMC: 2834169. DOI: 10.1016/j.jacc.2009.09.009. View

11.

Brunet A, Sweeney L, Sturgill J, Chua K, Greer P, Lin Y . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666):2011-5. DOI: 10.1126/science.1094637. View

12.

Kabir S, Hockemeyer D, de Lange T . TALEN gene knockouts reveal no requirement for the conserved human shelterin protein Rap1 in telomere protection and length regulation. Cell Rep. 2014; 9(4):1273-80. PMC: 4254571. DOI: 10.1016/j.celrep.2014.10.014. View

13.

Hardy C, Sussel L, Shore D . A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation. Genes Dev. 1992; 6(5):801-14. DOI: 10.1101/gad.6.5.801. View

14.

Tedgui A, Mallat Z . Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006; 86(2):515-81. DOI: 10.1152/physrev.00024.2005. View

15.

Hanaoka S, Nagadoi A, Yoshimura S, Aimoto S, Li B, de Lange T . NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains. J Mol Biol. 2001; 312(1):167-75. DOI: 10.1006/jmbi.2001.4924. View

16.

van Steensel B, de Lange T . Control of telomere length by the human telomeric protein TRF1. Nature. 1997; 385(6618):740-3. DOI: 10.1038/385740a0. View

17.

Ghosh S, May M, Kopp E . NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16:225-60. DOI: 10.1146/annurev.immunol.16.1.225. View

18.

Rosa C, Xavier N, Henrique Campos D, Fernandes A, Cezar M, Martinez P . Diabetes mellitus activates fetal gene program and intensifies cardiac remodeling and oxidative stress in aged spontaneously hypertensive rats. Cardiovasc Diabetol. 2013; 12:152. PMC: 4015448. DOI: 10.1186/1475-2840-12-152. View

19.

Nishikawa T, Edelstein D, Du X, Yamagishi S, Matsumura T, Kaneda Y . Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000; 404(6779):787-90. DOI: 10.1038/35008121. View

20.

Levy M, Allsopp R, Futcher A, Greider C, Harley C . Telomere end-replication problem and cell aging. J Mol Biol. 1992; 225(4):951-60. DOI: 10.1016/0022-2836(92)90096-3. View