Central European Journal of Sport Sciences and Medicine

ISSN: 2300-9705     eISSN: 2353-2807    OAI    DOI: 10.18276/cej.2019.4-09
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Issue archive / Vol. 28, No. 4/2019
The Modulatory Effect of Physical Activity on APE1-Mediated Telomere Length and Stability; A Narrative Review

Authors: Gabriela Betlej
College of Medical Sciences, Institute of Physical Culture Studies, University of Rzeszow, Rzeszow, Poland

Aleksandra Kwiatkowska
College of Medical Sciences, Institute of Physical Culture Studies, University of Rzeszow, Rzeszow, Poland

Ewelina Bator
College of Medical Sciences, Institute of Physical Culture Studies, University of Rzeszow, Rzeszow, Poland
Keywords: physical activity telomeres BER DNA repair APE1 oxidative stress
Year of publication:2019
Page range:10 (97-106)
Cited-by (Crossref) ?:


Physical activity is associated with enhanced generation of reactive oxygen species (ROS) that, in turn, can play a dual role in the human body. Upon physiological conditions, ROS act as secondary messengers in different cell signaling pathways. In contrast, ROS overexpression can lead to oxidative stress and oxidative stress-associated harmful consequences. This exercise-induced interplay among oxidants and antioxidants can modulate numerous physiological and molecular mechanisms, for example telomere length maintenance and stability. The latter is, in turn, under strict control of oxidative stress-activated base excision repair (BER) pathway, one of the DNA repair mechanisms; and growing evidence directs attention to apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional BER protein. Therefore, this review intends to address several issues concerning modulatory effect of exercise on APE1-mediated telomere length maintenance and redox activities.
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1.Aguiar, S.S., Rosa, T.S., Sousa, C.V., Santos, P.A., Barbosa, L.P., Deus, L.A., Rosa, E.C., Andrade, R.V., Simoes, H.G. (2019). Influence of Body Fat on Oxidative Stress and Telomere Length of Master Athletes. Journal of strength and conditioning research.
2.Babinský, M., Fiala, R., Kejnovská, I., Bednářová, K., Marek, R., Sagi, J., Sklenar, V., Vorlickova, M. (2014). Loss of loop adenines alters human telomere dAG3(TTAG3)3 quadruplex folding. Nucleic acids research, 42 (22), 14031–14041.
3.Baumann, P., Cech, T.R. (2001). Pot1, the putative telomere end-binding protein in fission yeast and humans. Science (New York, N.Y.), 292 (5519), 1171–1175.
4.Blackburn, E.H. (2005). Telomeres and telomerase. Their mechanisms of action and the effects of altering their functions. FEBS letters, 579 (4), 859–862.
5.Blasco, M.A. (2003). Mammalian telomeres and telomerase. Why they matter for cancer and aging.European journal of cell biology, 82 (9), 441–446.
6.Bochman, M.L., Paeschke, K., Zakian, V.A. (2012). DNA secondary structures. Stability and function of G-quadruplex structures. Nature reviews. Genetics, 13 (11), 770–780.
7.Bonomini, F., Rodella, L.F., Rezzani, R. (2015). Metabolic syndrome, aging and involvement of oxidative stress. Aging and disease, 6 (2), 109–120.
8.Borghini, A., Giardini, G., Tonacci, A., Mastorci, F., Mercuri, A., Mrakic-Sposta, S., Moretti, S., Andreassi, M.G., Pratali, L. (2015). Chronic and acute effects of endurance training on telomere length. Mutagenesis, 30 (5), 711–716.
9.Broxson, C., Hayner, J.N., Beckett, J., Bloom, L.B., Tornaletti, S. (2014). Human AP endonuclease inefficiently removes abasic sites within G4 structures compared to duplex DNA. Nucleic acids research, 42 (12), 7708–7719.
10.Bugaut, A., Alberti, P. (2015). Understanding the stability of DNA G-quadruplex units in long human telomeric strands. Biochimie, 113, 125–133.
11.Burra, S., Marasco, D., Malfatti, M.C., Antoniali, G., Virgilio, A., Esposito, V., Demple, B., Galeone, A., Tell, G. (2019). Human AP-endonuclease (Ape1) activity on telomeric G4 structures is modulated by acetylatable lysine residues in the N-terminal sequence. DNA repair, 73, 129–143.
12.Chilton, W.L., Marques, F.Z., West, J., Kannourakis, G., Berzins, S.P., O'Brien, B.J., Charchar, F.J. (2014). Acute exercise leads to regulation of telomere-associated genes and microRNA expression in immune cells. PloS one, 9 (4).
13.Claussin, C., Chang, M. (2015). The many facets of homologous recombination at telomeres. Microbial cell (Graz, Austria), 2 (9), 308–321.
14.David, S.S., O’Shea, V.L., Kundu, S. (2007). Base Excision Repair of Oxidative DNA Damage. Nature, 447 (7147), 941–950.
15.De Lange, T. (2005). Shelterin. The protein complex that shapes and safeguards human telomeres. Genes & development, 19 (18), 2100–2110.
16.De Lange, T. (2009). How telomeres solve the end-protection problem. Science (New York, N.Y.), 326 (5955), 948–952.
17.Denchi, E.L., de Lange, T. (2007): Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature, 448 (7157), 1068–1071.
18.Denham, J., Nelson, C.P., O'Brien, B.J., Nankervis, S.A., Denniff, M., Harvey, J.T., Marques, F.Z., Codd, V., Zukowska-Szczechowska, E., Samani, N.J., Tomaszewski, M., Charchar, F.J. (2013). Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors. PloS one, 8 (7).
19.Dhalla, N.S., Temsah, R.M., Netticadan, T. (2000). Role of oxidative stress in cardiovascular diseases. Journal of hypertension, 18 (6), 655–673.
20.Du, M., Prescott, J., Kraft, P., Han, J., Giovannucci, E., Hankinson, S.E., de Vivo, I. (2012). Physical activity, sedentary behavior, and leukocyte telomere length in women. American journal of epidemiology, 175 (5), 414–422.
21.Edwards, M.K., Loprinzi, P.D. (2017). Sedentary behavior, physical activity and cardiorespiratory fitness on leukocyte telomere length. Health promotion perspectives, 7 (1), 22–27.
22.Griffith, J.D., Comeau, L., Rosenfield, S., Stansel, R.M., Bianchi, A., Moss, H., de Lange, T. (1999). Mammalian telomeres end in a large duplex loop. Cell, 97 (4), 503–514.
23.Harley, C.B., Futcher, A.B., Greider, C.W. (1990). Telomeres shorten during ageing of human fibroblasts. Nature, 345 (6274), 458–460.
24.Jackson, S.P., Bartek, J. (2009). The DNA-damage response in human biology and disease. Nature, 461 (7267), 1071–1078.
25.Jia, P., Her, C., Chai, W. (2015). DNA Excision Repair at Telomeres. DNA Repair, 36, 137–145.
26.Krokan, H.E., Bjørås, M. (2013). Base excision repair. Cold Spring Harbor perspectives in biology, 5 (4).
27.LaRocca, T J., Seals, D.R., Pierce, G.L. (2010). Leukocyte telomere length is preserved with aging in endurance exercise-trained adults and related to maximal aerobic capacity. Mechanisms of ageing and development, 131 (2), 165–167.
28.Latifovic, L., Peacock, S.D., Massey, T.E., King, W.D. (2016). The Influence of Alcohol Consumption, Cigarette Smoking, and Physical Activity on Leukocyte Telomere Length. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 25 (2), 374–380.
29.Laye, M.J., Solomon, T.P.J., Karstoft, K., Pedersen, K.K., Nielsen, S.D., Pedersen, B.K. (2012). Increased shelterin mRNA expression in peripheral blood mononuclear cells and skeletal muscle following an ultra-long-distance running event. Journal of applied physiology (Bethesda, Md.: 1985), 112 (5), 773–781.
30.Li, M., Wilson, D.M. (2014). Human apurinic/apyrimidinic endonuclease 1. Antioxidants & redox signaling, 20 (4), 678–707.
31.Li, M., Yang, X., Lu, X., Dai, N., Zhang, S., Cheng, Y., Zhang, L., Yang, Y., Liu, Y., Wang, D., Wilson, D.M. (2018). APE1 deficiency promotes cellular senescence and premature aging features. Nucleic acids research, 46 (11), 5664–5677.
32.Ludlow, A.T., Ludlow, L.W., Roth, S.M. (2013). Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins. BioMed research international.
33.Madlener, S., Ströbel, T., Vose, S., Saydam, O., Price, B.D., Demple, B., Saydam, N. (2013). Essential role for mammalian apurinic/apyrimidinic (AP) endonuclease Ape1/Ref-1 in telomere maintenance. Proceedings of the National Academy of Sciences of the United States of America, 110 (44), 17844–17849.
34.Marcand, S. (2014). How do telomeres and NHEJ coexist? Molecular & cellular oncology, 1 (3).
35.Mason, C., Risques, R.A., Xiao, L., Duggan, C.R., Imayama, I., Campbell, K.L., Kong, A., Foster-Schubert, K.E., Wang, C.Y., Alfano, C.M., Blackburn, G.L., Rabinovitch, P.S., McTiernan, A. (2013). Independent and combined effects of dietary weight loss and exercise on leukocyte telomere length in postmenopausal women. Obesity (Silver Spring, Md.), 21 (12).
36.Miller, A.S., Balakrishnan, L., Buncher, N.A., Opresko, P.L., Bambara, R.A. (2012). Telomere proteins POT1, TRF1 and TRF2 augment long-patch base excision repair in vitro. Cell cycle (Georgetown, Tex.), 11 (5), 998–1007.
37.Mundstock, E., Zatti, H., Louzada, F.M., Oliveira, S.G., Guma, F.T.C.R., Paris, M.M., Rueda, A. B., Machado, D.G., Stein, R.T., Jones, M.H., Sarria, E.E., Barbe-Tuana, F.M., Mattiello, R. (2015). Effects of physical activity in telomere length. Systematic review and meta-analysis. Ageing research reviews, 22, 72–80.
38.Muniesa, C.A., Verde, Z., Diaz-Ureña, G., Santiago, C., Gutiérrez, F., Díaz, E., Gomez-Gallego, F., Pareja-Galeano, H., Soares-Miranda, L., Lucia A. (2017). Telomere Length in Elite Athletes. International journal of sports physiology and performance, 12 (7), 994–996.
39.Oikawa, S., Kawanishi, S. (1999). Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS letters, 453 (3), 365–368.
40.Olovnikov, A.M. (1971). Printsip marginotomii v matrichnom sinteze polinukleotidov. Doklady Akademii nauk SSSR, 201 (6), 1496–1499.
41.Opresko, P.L., Fan, J., Danzy, S., Wilson, D.M., Bohr, V.A. (2005). Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2. Nucleic acids research, 33 (4), 1230–1239.
42.Palm, W., de Lange, T. (2008). How shelterin protects mammalian telomeres. Annual review of genetics, 42, 301–334.
43.Poletto, M., Vascotto, C., Scognamiglio, P.L., Lirussi, L., Marasco, D., Tell, G. (2013). Role of the unstructured N-terminal domain of the hAPE1 (human apurinic/apyrimidinic endonuclease 1) in the modulation of its interaction with nucleic acids and NPM1 (nucleophosmin). The Biochemical journal, 452 (3), 545–557.
44.Powers, S.K., Jackson, M.J. (2008). Exercise-induced oxidative stress. Cellular mechanisms and impact on muscle force production. Physiological reviews, 88 (4), 1243–1276.
45.Radak, Z., Bori, Z., Koltai, E., Fatouros, I.G., Jamurtas, A.Z., Douroudos, I.I., Terzis, G., Nikolaidis, M.G., Chatzinikolaou, A., Sovatzidis, A., Kumagai, S., Naito, H., Boldogh, I. (2011). Age-dependent changes in 8-oxoguanine-DNA glycosylase activity are modulated by adaptive responses to physical exercise in human skeletal muscle. Free radical biology & medicine, 51 (2), 417–423.
46.Radak, Z., Chung, H.Y., Goto, S. (2005). Exercise and hormesis. Oxidative stress-related adaptation for successful aging. Biogerontology, 6 (1), 71–75.
47.Reuter, S., Gupta, S.C., Chaturvedi, M.M., Aggarwal, B.B. (2010). Oxidative stress, inflammation, and cancer. How are they linked? Free radical biology & medicine, 49 (11), 1603–1616.
48.Robson, C.N., Hochhauser, D., Craig, R., Rack, K., Buckle, V.J., Hickson, I.D. (1992). Structure of the human DNA repair gene HAP1 and its localisation to chromosome 14q 11.2-12. Nucleic acids research, 20 (17), 4417–4421.
49.Ścibior-Bentkowska, D., Czeczot, H. (2009). Komórki nowotworowe a stres oksydacyjny. Postępy higieny i medycyny doświadczalnej (Online), 63, 58–72.
50.Shin, Y.A., Lee, J.H., Song, W., Jun, T.W. (2008). Exercise training improves the antioxidant enzyme activity with no changes of telomere length. Mechanisms of ageing and development, 129 (5), 254–260.
51.Schmidt, R.H., Nickerson, J.M., Boatright, J.H. (2016). Exercise as Gene Therapy: BDNF and DNA Damage Repair. Asia Pac J Ophthalmoll, 5 (4), 309–311.
52.Simoes, H.G., Sousa, C.V., Dos Santos Rosa, T., da Silva Aguiar, S., Deus, L.A., Rosa, E.C.C.C., Amato, A.A., Andrade, R.V. (2017). Longer Telomere Length in Elite Master Sprinters. Relationship to Performance and Body Composition. International journal of sports medicine, 38 (14), 1111–1116.
53.Sorce, S., Krause, K.H. (2009). NOX enzymes in the central nervous system. From signaling to disease. Antioxidants & redox signaling, 11 (10), 2481–2504.
54.Tell, G., Quadrifoglio, F., Tiribelli, C., Kelley, M.R. (2009). The Many Functions of APE1/Ref-1: Not Only a DNA Repair Enzyme. Antioxid Redox Signal., 11 (3), 601–619.
55.Wang, Z., Rhee, D.B., Lu, J., Bohr, C.T., Zhou, F., Vallabhaneni, H., de Souza-Pinto, N.C., Liu Y. (2010). Characterization of Oxidative Guanine Damage and Repair in Mammalian Telomeres. PLoS Genet., 6 (5).
56.Watson, J.D. (1972). Origin of concatemeric T7 DNA. Nature: New biology, 239 (94), 197–201.
57.Webb, C.J., Wu, Y., Zakian, V.A. (2013). DNA Repair at Telomeres: Keeping the Ends Intact. In: Cold Spring Harb Perspect Biol., 5 (6).
58.Werner, C., Fürster, T., Widmann, T., Pöss, J., Roggia, C., Hanhoun, M., Scharhag, J., Buchner, N., Meyer, T., Kindermann, W., Haendeler, J., Böhm, M., Laufs, U. (2009). Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation, 120 (24), 2438–2447.
59.Werner, C.M., Hecksteden, A., Morsch, A., Zundler, J., Wegmann, M., Kratzsch, J., Thiery, J., Hohl, M., Bittenbring, J-T., Neumann, F., Böhm, M., Meyer, T., Laufs, U. (2019). Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study. European heart journal, 40 (1), 34–46.
60.Xanthoudakis, S., Miao, G.G., Curran, T. (1994). The redox and DNA-repair activities of Ref-1 are encoded by nonoverlapping domains. Proceedings of the National Academy of Sciences of the United States of America, 91 (1), 23–27.
61.Xanthoudakis, S., Smeyne, R.J., Wallace, J.D., Curran, T. (1996). The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proceedings of the National Academy of Sciences of the United States of America, 93 (17), 8919–8923.
62.Yang, J-L., Yu-Lin, T., Chuang, P-C., Bohr, V.A., Mattson, M.P. (2014). BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1. Neuromolecular Med., 16 (1), 161–174.
63.Zahler, A.M., Williamson, J.R., Cech, T.R., Prescott, D.M. (1991). Inhibition of telomerase by G-quartet DNA structures. Nature, 350 (6320), 718–720.
64.Zglinicki, T., Pilger, R., Sitte, N. (2000). Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radical Biology and Medicine, 28 (1), 64–74.
65.Zuo, L., Hallman, A.H., Yousif, M.K., Chien, M.T. (2012). Oxidative stress, respiratory muscle dysfunction, and potential therapeutics in chronic obstructive pulmonary disease. Front. Biol., 7 (6), 506–513.