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3. Impact of Simulated Rotating Shift Work on Mammary Tumor Development in the p53R270H©/+WAPCre Mouse Model for Breast Cancer

Author

Streng, Astrid A, Van Dycke, Kirsten C G, van Oostrom, Conny T M, Salvatori, Daniela C F, Hulsegge, Gerben, Chaves, Inês, Roenneberg, Till, Zander, Serge A L, van Steeg, Harry, van der Horst, Gijsbertus T J, van Kerkhof, Linda W M, Streng, Astrid A, Van Dycke, Kirsten C G, van Oostrom, Conny T M, Salvatori, Daniela C F, Hulsegge, Gerben, Chaves, Inês, Roenneberg, Till, Zander, Serge A L, van Steeg, Harry, van der Horst, Gijsbertus T J, and van Kerkhof, Linda W M

Abstract

Epidemiological studies associate night shift work with increased breast cancer risk. However, the underlying mechanisms are not clearly understood. To better understand these mechanisms, animal models that mimic the human situation of different aspects of shift work are needed. In this study, we used "timed sleep restriction" (TSR) cages to simulate clockwise and counterclockwise rotating shift work schedules and investigated predicted sleep patterns and mammary tumor development in breast tumor-prone female p53R270H©/+WAPCre mice. We show that TSR cages are effective in disturbing normal activity and estimated sleep patterns. Although circadian rhythms were not shifted, we observed effects of the rotating schedules on sleep timing and sleep duration. Sleep loss during a simulated shift was partly compensated after the shift and also partly during the free days. No effects were observed on body weight gain and latency time of breast cancer development. In summary, our study shows that the TSR cages can be used to model shift work in mice and affect patterns of activity and sleep. The effect of disturbing sleep patterns on carcinogenesis needs to be further investigated.

Published
2023

4. Impact of Simulated Rotating Shift Work on Mammary Tumor Development in the p53R270H©/+WAPCre Mouse Model for Breast Cancer

Author

CS_Cancer, CS_Locomotion, Anatomie en fysiologie, Locomotion - Integrating Sciences, Streng, Astrid A, Van Dycke, Kirsten C G, van Oostrom, Conny T M, Salvatori, Daniela C F, Hulsegge, Gerben, Chaves, Inês, Roenneberg, Till, Zander, Serge A L, van Steeg, Harry, van der Horst, Gijsbertus T J, van Kerkhof, Linda W M, CS_Cancer, CS_Locomotion, Anatomie en fysiologie, Locomotion - Integrating Sciences, Streng, Astrid A, Van Dycke, Kirsten C G, van Oostrom, Conny T M, Salvatori, Daniela C F, Hulsegge, Gerben, Chaves, Inês, Roenneberg, Till, Zander, Serge A L, van Steeg, Harry, van der Horst, Gijsbertus T J, and van Kerkhof, Linda W M

Published
2023

6. Impact of Simulated Rotating Shift Work on Mammary Tumor Development in the p53 R270H©/+ WAPCre Mouse Model for Breast Cancer.

Author

Streng, Astrid A., Van Dycke, Kirsten C. G., van Oostrom, Conny T. M., Salvatori, Daniela C. F., Hulsegge, Gerben, Chaves, Inês, Roenneberg, Till, Zander, Serge A. L., van Steeg, Harry, van der Horst, Gijsbertus T. J., and van Kerkhof, Linda W. M.

Subjects
SHIFT systems, SLEEP duration, MICE, BREAST cancer, LABORATORY mice, ANIMAL disease models
Abstract

Epidemiological studies associate night shift work with increased breast cancer risk. However, the underlying mechanisms are not clearly understood. To better understand these mechanisms, animal models that mimic the human situation of different aspects of shift work are needed. In this study, we used "timed sleep restriction" (TSR) cages to simulate clockwise and counterclockwise rotating shift work schedules and investigated predicted sleep patterns and mammary tumor development in breast tumor–prone female p53 R270H©/+ WAPCre mice. We show that TSR cages are effective in disturbing normal activity and estimated sleep patterns. Although circadian rhythms were not shifted, we observed effects of the rotating schedules on sleep timing and sleep duration. Sleep loss during a simulated shift was partly compensated after the shift and also partly during the free days. No effects were observed on body weight gain and latency time of breast cancer development. In summary, our study shows that the TSR cages can be used to model shift work in mice and affect patterns of activity and sleep. The effect of disturbing sleep patterns on carcinogenesis needs to be further investigated. [ABSTRACT FROM AUTHOR]

Published
2023
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14. Photorepair of Either CPD or 6-4PP DNA Lesions in Basal Keratinocytes Attenuates Ultraviolet-Induced Skin Effects in Nucleotide Excision Repair Deficient Mice

Author

Kajitani, Gustavo S., Quayle, Carolina, Garcia, Camila C. M., Fotoran, Wesley L., dos Santos, Juliana F. R., van der Horst, Gijsbertus T. J., Hoeijmakers, Jan H. J., Menck, Carlos F. M., Kajitani, Gustavo S., Quayle, Carolina, Garcia, Camila C. M., Fotoran, Wesley L., dos Santos, Juliana F. R., van der Horst, Gijsbertus T. J., Hoeijmakers, Jan H. J., and Menck, Carlos F. M.

Abstract

Ultraviolet (UV) radiation is one of the most genotoxic, universal agents present in the environment. UVB (280-315 nm) radiation directly damages DNA, producing cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs). These photolesions interfere with essential cellular processes by blocking transcription and replication polymerases, and may induce skin inflammation, hyperplasia and cell death eventually contributing to skin aging, effects mediated mainly by keratinocytes. Additionally, these lesions may also induce mutations and thereby cause skin cancer. Photolesions are repaired by the Nucleotide Excision Repair (NER) pathway, responsible for repairing bulky DNA lesions. Both types of photolesions can also be repaired by distinct (CPD- or 6-4PP-) photolyases, enzymes that specifically repair their respective photolesion by directly splitting each dimer through a light-dependent process termed photoreactivation. However, as photolyases are absent in placental mammals, these organisms depend solely on NER for the repair of DNA UV lesions. However, the individual contribution of each UV dimer in the skin effects, as well as the role of keratinocytes has remained elusive. In this study, we show that in NER-deficient mice, the transgenic expression and photorepair of CPD-photolyase in basal keratinocytes completely inhibited UVB-induced epidermal thickness and cell proliferation. On the other hand, photorepair by 6-4PP-photolyase in keratinocytes reduced but did not abrogate these UV-induced effects. The photolyase mediated removal of either CPDs or 6-4PPs from basal keratinocytes in the skin also reduced UVB-induced apoptosis, ICAM-1 expression, and myeloperoxidase activation. These findings indicate that, in NER-deficient rodents, both types of photolesions have causal roles in UVB-induced epidermal cell proliferation, hyperplasia, cell death and inflammation. Furthermore, these findings also support the notion that basal keratinocy

Published
2022

21. Circadian behavioral rhythms in Cry1/Cry2 double-deficient mice induced by methamphetamine

Author

Honma, Sato, Yasuda, Tsubura, Yasui, Akira, van der Horst, Gijsbertus T. J., and Honma, Ken-ichi

Subjects
Animal behavior -- Physiological aspects -- Research, Gene expression -- Physiological aspects -- Research, Methamphetamine -- Dosage and administration -- Physiological aspects -- Research, Circadian rhythms -- Physiological aspects -- Research, Cytochromes -- Physiological aspects -- Research, Biological sciences, Physiological aspects, Research, Dosage and administration
Abstract

Byline: Sato Honma (Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, sathonma@med.hokudai.ac.jp); Tsubura Yasuda (Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan); Akira Yasui [...]

Published
2008
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23. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis

Author

Niedernhofer, Laura J., Garinis, George A., Raams, Anja, Lalai, Astrid S., Robinson, Andria Rasile, Appeldoorn, Esther, Odijk, Hanny, Oostendorp, Roos, Ahmad, Anwaar, van Leeuwen, Wibeke, Theil, Arjan F., Vermeulen, Wim, van der Horst, Gijsbertus T. J., Meinecke, Peter, Kleijer, Wim J., Vijg, Jan, Jaspers, Nicolaas G. J., and Hoeijmakers, Jan H. J.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Laura J. Niedernhofer [1, 4]; George A. Garinis [1]; Anja Raams [1]; Astrid S. Lalai [1]; Andria Rasile Robinson [4]; Esther Appeldoorn [1]; Hanny Odijk [1]; Roos Oostendorp [1]; [...]

Published
2006
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28. Circadian Variation in Human Milk Composition, a Systematic Review

Author

Italianer, Merel F., primary, Naninck, Eva F. G., additional, Roelants, Jorine A., additional, van der Horst, Gijsbertus T. J., additional, Reiss, Irwin K. M., additional, Goudoever, Johannes B. van, additional, Joosten, Koen F. M., additional, Chaves, Inês, additional, and Vermeulen, Marijn J., additional

Published
2020
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29. Understanding the association between sleep, shift work and COVID‐19 vaccine immune response efficacy: Protocol of the S‐CORE study.

Author

Lammers‐van der Holst, Heidi M., Lammers, Gert Jan, van der Horst, Gijsbertus T. J., Chaves, Inês, de Vries, Rory D., GeurtsvanKessel, Corine H., Koch, Birgit, and van der Kuy, Hugo M.

Subjects
COVID-19, VACCINE effectiveness, SARS-CoV-2, SHIFT systems, COVID-19 vaccines, IMMUNE response
Abstract

Summary: This protocol describes an innovative study to investigate the relationship between sleep, shift work and the immune response to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2; coronavirus disease 2019 [COVID‐19]) vaccination. As the COVID‐19 pandemic is a global crisis with devastating health, social and economic impacts, there is a pressing need for effective vaccination programmes. Previous influenza and hepatitis vaccination studies suggest that lack of sleep can negatively alter immune responsiveness, while circadian misalignment most likely may also play an important role in the immune response to vaccination. Our present study will be the first to address this question in actual shift workers and in relation to COVID‐19 vaccination. We hypothesise that the occurrence of recent night shifts and diminished sleep will negatively alter the immune response to vaccination in shift workers compared to dayworkers. We aim to recruit 50 shift workers and 50 dayworkers. Participants will receive an mRNA‐based vaccination, through the Dutch vaccination programme. To assess immune responsiveness, blood will be drawn at baseline (before first vaccination), 10 days after first vaccination, the day prior to the second vaccination; and 28 days, 6 and 12 months after the second vaccination. Actigraphy and daily sleep e‐diaries will be implemented for 7 days around each vaccination to assess sleep. The Pittsburgh Sleep Quality Index will be used to monitor sleep in the long term. Optimising the efficacy of the COVID‐19 vaccines is of outmost importance and results of this study could provide insights to develop sleep and circadian‐based interventions to enhance vaccination immunity, and thereby improve global health. [ABSTRACT FROM AUTHOR]

Published
2022
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32. Premature Aging in Mice Deficient in DNA Repair and Transcription

Author

de Boer, Jan, Andressoo, Jaan Olle, de Wit, Jan, Huijmans, Jan, Beems, Rudolph B., van Steeg, Harry, Weeda, Geert, van der Horst, Gijsbertus T. J., van Leeuwen, Wibeke, Themmen, Axel P. N., Meradji, Morteza, and Hoeijmakers, Jan H. J.

Published
2002

37. Interacting Molecular Loops in the Mammalian Circadian Clock

Author

Shearman, Lauren P., Sriram, Sathyanarayanan, Weaver, David R., Maywood, Elizabeth S., Chaves, Ines, Zheng, Binhai, Kume, Kazuhiko, Lee, Cheng Chi, van der Horst, Gijsbertus T. J., Hastings, Michael H., and Reppert, Steven M.

Published
2000

40. Gestational jet lag predisposes to later-life skeletal and cardiac disease

Author

Chaves, Inês, primary, van der Eerden, Bram, additional, Boers, Ruben, additional, Boers, Joachim, additional, Streng, Astrid A., additional, Ridwan, Yanto, additional, Schreuders-Koedam, Marijke, additional, Vermeulen, Marijn, additional, van der Pluijm, Ingrid, additional, Essers, Jeroen, additional, Gribnau, Joost, additional, Reiss, Irwin K. M., additional, and van der Horst, Gijsbertus T. J., additional

Published
2019
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42. Phase responses to light pulses in mice lacking functional per or cry genes

Author

Spoelstra, Kamiel, Albrecht, Urs, van der Horst, Gijsbertus T J, Brauer, Verena, Daan, Serge, Horst, Gijsbertus T.J. van der, Beersma lab, Ocean Ecosystems, Weissing group, Animal Ecology (AnE), and Institute of Ecological Research (IOO)

Subjects
Male, 0301 basic medicine, Time Factors, Cry1, Light, Cry2, Physiology, Mutant, Circadian clock, CLOCK, Cell Cycle Proteins, MOUSE, Mice, 0302 clinical medicine, Cryptochrome, NOCTURNAL RODENTS, CIRCADIAN PACEMAKERS, Mice, Knockout, Genetics, Nuclear Proteins, Per2, Period Circadian Proteins, Per1, Phase resetting, Circadian Rhythm, PER2, PER1, OSCILLATOR, medicine.medical_specialty, animal structures, Biology, 03 medical and health sciences, Biological Clocks, Physiology (medical), Internal medicine, medicine, SEASONS, Animals, Circadian rhythm, NUCLEUS, Flavoproteins, RHYTHMICITY, Wild type, SHIFTS, MPER2, Cryptochromes, 030104 developmental biology, Endocrinology, PRC, 030217 neurology & neurosurgery
Abstract

The phase-resetting properties of the circadian system in mice with a functional deletion in mCry1, mCry2, mPer1, or mPer2 were studied in 2 experiments. In experiment 1, mCry1-/- and mCry2-/- mice as well as mPer1Brdm1 and mPer2Brdm1 mutant mice were exposed to 15-min light pulses during the 1st cycle following entrainment, either early (external time [ExT] 20) or late (ExT 4) in the subjective night. In experiment 2, a full PRC was measured for all these strains by exposure to light pulses of the same duration and intensity in free-running conditions in constant darkness. Directly after entrainment (experiment 1), mPer1Brdm1 animals did not show significant phase advances by a light pulse in the late subjective night (ExT 4), as in the study by Albrecht et al. In the same experiment, mPer2Brdm1 mice became arrhythmic too frequently to reliably measure their phase responses. Mice with a targeted gene disruption in mCry1 or mCry2 showed increased phase delays compared to wild type after exposure to a light pulse in the early subjective night (ExT 20). Otherwise, phase shifts were not significantly affected. In free run (experiment 2), all genotypes did show phase advances and phase delays. The mPer2Brdm1 mutant PRC was above the mPer1Brdm1 mutant and wild-type PRC (i.e., less delayed and more advanced) at most circadian phases. The mPer1Brdm1 mutant PRC was not distinguishable from the wildtype PRC. The mCry2-/- mice showed much smaller phase delays than did mCry1-/- mice in the subjective evening (delay phase). In general, mPer2Brdm1 mutant mice were more accelerated by light compared to mPer1Brdm1 and wildtype control mice, whereas mCry1-/- mice were more delayed by light than were mCry2-/- mice.

Published
2004
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43. Differential role of transcription-coupled repair in UVB-induced [G.sub.2] arrest and apoptosis in mouse epidermis

Author

van Oosten, Marijke, Rebel, Heggert, Friedberg, Errol C., van Steeg, Harry, van der Horst, Gijsbertus T. J., van Kranen, Henk J., Westerman, Anja, van Zeeland, Albert A., Mullenders, Leon H. F., and de Gruijl, Frank R.

Subjects
Cellular control mechanisms -- Research, Ultraviolet radiation -- Physiological aspects, Defense reaction (Physiology) -- Research, Cell death -- Research, DNA repair -- Research, Genetic disorders -- Causes of, Epidermis -- Research, Mice -- Genetic aspects, Science and technology
Abstract

Nucleotide excision repair (NER), apoptosis, and cell-cycle regulation are major defense mechanisms against the carcinogenic effects of UVB light. NER eliminates UVB-induced DNA photolesions via two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). Defects in NER result in the human disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS), displaying severe UV sensitivity and in the case of XP, cancer proneness. We investigated the impact of deficiencies in NER subpathways on apoptosis, hyperplasia, and cell cycle progression in the epidermis of UVB-exposed CS group B ([Csb.sup.-/-]) mice (no TCR), XP group C ([Xpc.sup.-/-]) mice (no GGR), and XP group A ([Xpa.sup.-/-]) mice (no TCR and no GGR). On UVB treatment (250 J/[m.sup.2]), [Xpa.sup.-/-] and [Csb.sup.-/-] mice revealed an extensive apoptotic response in the skin, a blockage of cell cycle progression of epidermal cells, and strong hyperplasia. Interestingly, the absence of this apoptotic response in the skin of wild-type and [Xpc.sup.-/-] mice coincided with the ability of epidermal cells to enter the S phase. However, only epidermal cells of [Xpc.sup.-/-] mice subsequently became arrested in the [G.sub.2] phase. Our data demonstrate that TCR (and/or restoration of UVB-inhibited transcription) enables damaged cells to progress through S phase and prevents the induction of apoptosis and hyperplasia. [G.sub.2] arrest is manifest only under conditions of proficient TCR in combination with deficient GGR, indicating that epidermal cells become arrested in the [G.sub.2] phase as a result of persisting damage in their genome.

Published
2000

44. Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

Author

Visser, W. Edward, Bombardieri, Cíntia R., Zevenbergen, Chantal, Barnhoorn, Sander, Ottaviani, Alexandre, Van Der Pluijm, Ingrid, Brandt, Renata, Kaptein, Ellen, Van Heerebeek, Ramona, Van Toor, Hans, Garinis, George A., Peeters, Robin P., Medici, Marco, Van Ham, Willy, Vermeij, Wilbert P., De Waard, Monique C., De Krijger, Ronald R., Boelen, Anita, Kwakkel, Joan, Kopchick, John J., List, Edward O., Melis, Joost P M, Darras, Veerle M., Dollé, Martijn E T, Van Der Horst, Gijsbertus T J, Hoeijmakers, Jan H J, Visser, Theo J., Visser, W. Edward, Bombardieri, Cíntia R., Zevenbergen, Chantal, Barnhoorn, Sander, Ottaviani, Alexandre, Van Der Pluijm, Ingrid, Brandt, Renata, Kaptein, Ellen, Van Heerebeek, Ramona, Van Toor, Hans, Garinis, George A., Peeters, Robin P., Medici, Marco, Van Ham, Willy, Vermeij, Wilbert P., De Waard, Monique C., De Krijger, Ronald R., Boelen, Anita, Kwakkel, Joan, Kopchick, John J., List, Edward O., Melis, Joost P M, Darras, Veerle M., Dollé, Martijn E T, Van Der Horst, Gijsbertus T J, Hoeijmakers, Jan H J, and Visser, Theo J.

Published
2016

45. Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

Author

Pathologie Pathologen staf, Visser, W. Edward, Bombardieri, Cíntia R., Zevenbergen, Chantal, Barnhoorn, Sander, Ottaviani, Alexandre, Van Der Pluijm, Ingrid, Brandt, Renata, Kaptein, Ellen, Van Heerebeek, Ramona, Van Toor, Hans, Garinis, George A., Peeters, Robin P., Medici, Marco, Van Ham, Willy, Vermeij, Wilbert P., De Waard, Monique C., De Krijger, Ronald R., Boelen, Anita, Kwakkel, Joan, Kopchick, John J., List, Edward O., Melis, Joost P M, Darras, Veerle M., Dollé, Martijn E T, Van Der Horst, Gijsbertus T J, Hoeijmakers, Jan H J, Visser, Theo J., Pathologie Pathologen staf, Visser, W. Edward, Bombardieri, Cíntia R., Zevenbergen, Chantal, Barnhoorn, Sander, Ottaviani, Alexandre, Van Der Pluijm, Ingrid, Brandt, Renata, Kaptein, Ellen, Van Heerebeek, Ramona, Van Toor, Hans, Garinis, George A., Peeters, Robin P., Medici, Marco, Van Ham, Willy, Vermeij, Wilbert P., De Waard, Monique C., De Krijger, Ronald R., Boelen, Anita, Kwakkel, Joan, Kopchick, John J., List, Edward O., Melis, Joost P M, Darras, Veerle M., Dollé, Martijn E T, Van Der Horst, Gijsbertus T J, Hoeijmakers, Jan H J, and Visser, Theo J.

Published
2016

47. Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging

Author

Visser, W. Edward, primary, Bombardieri, Cíntia R., additional, Zevenbergen, Chantal, additional, Barnhoorn, Sander, additional, Ottaviani, Alexandre, additional, van der Pluijm, Ingrid, additional, Brandt, Renata, additional, Kaptein, Ellen, additional, van Heerebeek, Ramona, additional, van Toor, Hans, additional, Garinis, George A., additional, Peeters, Robin P., additional, Medici, Marco, additional, van Ham, Willy, additional, Vermeij, Wilbert P., additional, de Waard, Monique C., additional, de Krijger, Ronald R., additional, Boelen, Anita, additional, Kwakkel, Joan, additional, Kopchick, John J., additional, List, Edward O., additional, Melis, Joost P. M., additional, Darras, Veerle M., additional, Dollé, Martijn E. T., additional, van der Horst, Gijsbertus T. J., additional, Hoeijmakers, Jan H. J., additional, and Visser, Theo J., additional

Published
2016
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48. The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1.

Author

Farshadi, Elham, Yan, Jie, Leclere, Pierre, Goldbeter, Albert, Chaves, Inês, and van der Horst, Gijsbertus T. J.

Abstract

We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down Bmal1 or Clock in NIH3T33C mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of Bmal1 resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of Bmal1 gene expression. In complete agreement with these experimental observations, simulation of Bmal1 knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating Cyclin B1 induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of Clock gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of Cyclin B1 expression. [ABSTRACT FROM AUTHOR]

Published
2019
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49. Differential roles for cryptochromes in the mammalian retinal clock.

Author

Wong, Jovi C. Y., Smyllie, Nicola J., Banks, Gareth T., Pothecary, Carina A., Barnard, Alun R., Maywood, Elizabeth S., Jagannath, Aarti, Hughes, Steven, van der Horst, Gijsbertus T. J., MacLaren, Robert E., Hankins, Mark W., Hastings, Michael H., Nolan, Patrick M., Foster, Russell G., and Peirson, Stuart N.

Published
2018
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50. Human papillomavirus mediated inhibition of DNA damage sensing and repair drives skin carcinogenesis

Author

Hufbauer, Martin, Cooke, James, van der Horst, Gijsbertus T. J., Pfister, Herbert, Storey, Alan, Akguel, Baki, Hufbauer, Martin, Cooke, James, van der Horst, Gijsbertus T. J., Pfister, Herbert, Storey, Alan, and Akguel, Baki

Abstract

Background: The failure to mount an effective DNA damage response to repair UV induced cyclobutane pyrimidine dimers (CPDs) results in an increased propensity to develop cutaneous squamous cell carcinoma (cSCC). High-risk patient groups, such as organ transplant recipients (OTRs) frequently exhibit field cancerization at UV exposed body sites from which multiple human papillomavirus (HPV)-associated cSCCs develop rapidly, leading to profound morbidity and increased mortality. In vitro molecular evidence indicates that HPV of genus beta-papillomavirus (beta-PV) play an important role in accelerating the early stages of skin tumorigenesis. Methods: We investigated the effects of UV induced DNA damage in murine models of beta-PV E6 oncoprotein driven skin tumorigenesis by crossing K14-HPV8-E6wt mice (developing skin tumors after UV treatment) with K14-CPD-photolyase animals and by generating the K14-HPV8-E6-K136N mutant mouse strain. Thymine dimers (marker for CPDs) and gamma H2AX (a marker for DNA double strand breaks) levels were determined in the murine skin and organotypic skin cultures of E6 expressing primary human keratinocytes after UV-irradiation by immunohistochemistry and in cell lines by In Cell Western blotting. Phosphorylation of ATR/Chk1 and ATM were assessed in cell lines and organotypic skin cultures by Western blots and immunohistochemistry. Results: Skin tumor development after UV-irradiation in K14-HPV8-E6wt mice could completely be blocked through expression of CPD-photolyase. Through quantification of thymine dimers after UV irradiation in cells expressing E6 proteins with point mutations at conserved residues we identified a critical lysine in the C-terminal part of the protein for prevention of DNA damage repair and p300 binding. Whereas all K14-HPV8-E6wt animals develop skin tumors after UV expression of the HPV8-E6-K136N mutant significantly blocked skin tumor development after UV treatment. The persistence of CPDs in hyperproliferative epider

Published
2015

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