The Role of External and Internal Stress on Telomere Length Regulation

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BORT, Anja, 2017. The Role of External and Internal Stress on Telomere Length Regulation [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Bort2017Exter-40726, title={The Role of External and Internal Stress on Telomere Length Regulation}, year={2017}, author={Bort, Anja}, address={Konstanz}, school={Universität Konstanz} }

2017 2017-11-23T14:03:44Z terms-of-use 2017-11-23T14:03:44Z The Role of External and Internal Stress on Telomere Length Regulation Bort, Anja eng Bort, Anja Telomere integrity is an important determinant for genomic stability in human cells. Excessive telomere shortening can be a first step towards cellular senescence, and abnormal telomere length regulation is defined as hallmark of cancer. So far, different internal and external stress factors have been investigated that may influences telomere length. The aim of this study was to determine the role of bariatric surgery-induced stress as well as acute and chronic UV-irradiation on telomere length.<br />It is suggested that obesity causes psychological and physiological stress which negatively affects telomere length in leukocytes. Bariatric intervention, with the result of significant weight loss, on the other hand, is known to alter telomere length and may revert the negative effect caused by obesity. To address this, we aimed to investigate telomere length regulation in PBMCs of morbidly obese patients undergoing bariatric intervention as well as healthy non-obese control probands. As result of the surgery, all obese patients showed highly significant weight loss. This did not immediately correlate with changes in telomere length; however, after 2 years an overall significant increase in telomere length was detected. We proposed that this increase in telomere length may be induced by a complex multi-factorial combination of key factors that reduced inflammation as well as oxidative stress and increased overall quality of life. Following telomere length regulation in the individual patient, we found large fluctuations from -38 % to +48 % during the 2-year observation time. Thus, telomere length regulation in these patients was not linear but a highly dynamic process. Investigating a control group of non-obese probands, we showed that this dynamics was not a consequence of intervention with obesity but was a general time-dependent regulatory consequence. Mechanistically, telomere length regulation in the control non-obese probands could be related to the individual “state of health”, as determined by a continuous questionnaire. Moreover, by multiplex cytokine ELISA of blood samples, the inflammatory cytokines IL-4 and IL-10 were identified as factors correlating negatively and IL-12 correlating positively with telomere length suggesting that these factors may drove a dissimilar proliferation of blood progenitor cells or regulated telomerase activity in the progenitor cells and thereby causing the observed variations (irregular oscillations) in telomere length.<br />Second, solar irradiation is a known exogenous stress stimulus acting directly on DNA as well as indirectly on various cellular targets. As a consequence, telomere shortening is supposed to occur at sites of sun-exposed skin. As the mechanism of the UV-induced telomere erosion remained largely elusive, the aim in this study was to investigate telomere length regulation upon UV-irradiation in human skin cells as well as in three-dimensional organotypic culture models. We showed that chronic UVA- and UVA+B-irradiation of organotypic skin cultures caused telomere shortening in p53-mutant HaCaT cells but not in normal human epidermal keratinocytes (NHEKs). Aiming at analyzing the acute effects of UV-irradiation, we found an early reactive oxygen species induction and unexpected chromatin modulation at the telomeres 1 h after irradiation in NHEK and after 48 h in HaCaT cells, which upon treatment with a histone deacetylase inhibitor could be identified as heterochromatin relaxation. Moreover, DNA damage repair proteins (γH2AX, 53BP1, ATM, PAR) accumulated at telomeres, confirming that UV-irradiation directly or indirectly damage telomeric DNA. While NHEK arrested in cell cycle, the p53-mutant HaCaT keratinocytes continued to proliferate with DNA damage. As proliferation is required to manifest telomere loss, it was tempting to suggest that in particular the p53-mutant cells suffer from UV-dependent telomere loss. Thereby, these cells either progress towards cellular senescence or genomic instability, a prerequisite for carcinogenesis.<br />In conclusion, our data confirmed that stress whether acting endogenously or being induced by exogenous factors, influenced telomere length as shown for bariatric intervention and weight loss of obese patients causing a time-dependent telomere elongation in their PBMCs as well as for chronic UV-induced stress causing accelerated telomere erosion in p53-mutant skin keratinocytes. Importantly, and for the first time, this study additionally demonstrated that telomere length in PBMCs is not static, but showed in as little as two-months-time intervals significant though irregular oscillation/fluctuation. This regulation is highly individual and needs to be taken into account when considering telomere length as a biomarker for instance in stress or disease. The mechanism of this native telomere length regulation, however, has not yet been fully understood and needs further investigation.

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