New toxicology: Carcinogenesis I

“Aude Sapere” “Dare to Know—HoraceThe first part of this three-part series deals with the history of the recognition of the origins of cancer in specific, mainly chemical, environmental factors; and the rapid advances made this century in identifying carcinogens and elucidating their modes of action. I will then go on to review, briefly, the most important groups of carcinogenic chemicals, their in-vivo activation and common mode of action.The second article will start with the cytotoxic drugs and demonstrate that the distinction between them and chemical carcinogens is arbitrary. I will also consider co-carcinogens and the carcinogenic action of UV light and the importance of these phenomena in understanding the genesis of cancer.Finally, I will look at the linked processes of resistance to cytotoxic drugs, defences against carcinogens and DNA repair processes which it may be possible to turn to therapeutic advantage.

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The ATPase Domain but Not the Acidic Region of Cockayne Syndrome Group B Gene Product Is Essential for DNA Repair

Molecular Biology of the Cell ◽

10.1091/mbc.10.11.3583 ◽

1999 ◽

Vol 10 (11) ◽

pp. 3583-3594 ◽

Cited By ~ 30

Author(s):

Robert M. Brosh ◽

Adayabalam S. Balajee ◽

Rebecca R. Selzer ◽

Morten Sunesen ◽

Luca Proietti De Santis ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Excision Repair ◽

Uv Light ◽

Genetic Disorder ◽

Cockayne Syndrome ◽

Premature Aging ◽

Atpase Domain ◽

Acidic Region

Cockayne syndrome (CS) is a human genetic disorder characterized by UV sensitivity, developmental abnormalities, and premature aging. Two of the genes involved, CSA andCSB, are required for transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes certain lesions rapidly and efficiently from the transcribed strand of active genes. CS proteins have also been implicated in the recovery of transcription after certain types of DNA damage such as those lesions induced by UV light. In this study, site-directed mutations have been introduced to the human CSB gene to investigate the functional significance of the conserved ATPase domain and of a highly acidic region of the protein. The CSB mutant alleles were tested for genetic complementation of UV-sensitive phenotypes in the human CS-B homologue of hamster UV61. In addition, theCSB mutant alleles were tested for their ability to complement the sensitivity of UV61 cells to the carcinogen 4-nitroquinoline-1-oxide (4-NQO), which introduces bulky DNA adducts repaired by global genome repair. Point mutation of a highly conserved glutamic acid residue in ATPase motif II abolished the ability of CSB protein to complement the UV-sensitive phenotypes of survival, RNA synthesis recovery, and gene-specific repair. These data indicate that the integrity of the ATPase domain is critical for CSB function in vivo. Likewise, the CSB ATPase point mutant failed to confer cellular resistance to 4-NQO, suggesting that ATP hydrolysis is required for CSB function in a TCR-independent pathway. On the contrary, a large deletion of the acidic region of CSB protein did not impair the genetic function in the processing of either UV- or 4-NQO-induced DNA damage. Thus the acidic region of CSB is likely to be dispensable for DNA repair, whereas the ATPase domain is essential for CSB function in both TCR-dependent and -independent pathways.

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p53-Dependent Regulation of Nucleotide Excision Repair in Murine Epidermis in vivo

Journal of Cutaneous Medicine and Surgery ◽

10.1177/120347549800300104 ◽

1998 ◽

Vol 3 (1) ◽

pp. 16-20 ◽

Cited By ~ 13

Author(s):

Victor A. Tron ◽

Martin J. Trotter ◽

Takatoshi Ishikawa ◽

Vincent C. Ho ◽

Gang Li

Keyword(s):

Dna Repair ◽

Excision Repair ◽

Uv Light ◽

Mouse Skin ◽

Computer Assisted ◽

Pyrimidine Dimers ◽

Cyclobutane Dimers ◽

Uv Dose ◽

Programed Cell Death

Background: p53 protects the integrity of the genome by inducing programed cell death or by promoting DNA repair. We have previously shown that loss or mutation of p53 leads to reduced DNA repair in keratinocytes. Objective: The hypothesis that p53 regulates repair of ultraviolet light-induced epidermal DNA damage in vivo was tested in mice. Methods: An immunohistochemical assay for pyrimidine dimers and 6–4 photoproducts was performed on ultraviolet-irradiated skin from p53 null (−/−) and wild type (+/+) mice. Immunostaining for photoproducts was quantified using computer-assisted imaging. The level of DNA repair was then expressed as the percentage of positive cells remaining as compared to the zero hour time point. Results: p53+/+ mouse skin exposed to 1000 J/m2 retained ≈ 25% of epidermal cyclobutane dimers at 48 h, whereas approximately 50% remained in p53−/− cells. Using the same UV dose, p53+/+ mice retained 20% of detectable 6–4 photoproducts by 24 h, whereas about 50% remained in epidermal cells of p53-deficient mice. Conclusion: Using in situ labelling of UV-damaged cells, we confirm our earlier conclusion that p53 regulates DNA repair within the epidermis after exposure to UV light.

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Shaping Vulnerable Bodies at the Thin Boundary between Environment and Organism: Skin, DNA Repair, and a Genealogy of DNA Care Strategies

Science in Context ◽

10.1017/s0269889715000162 ◽

2015 ◽

Vol 28 (3) ◽

pp. 427-464

Author(s):

Alexander von Schwerin

Keyword(s):

Dna Repair ◽

Molecular Level ◽

Uv Light ◽

Research Field ◽

The Body ◽

Research Areas ◽

Starting Point ◽

History Of ◽

The 1960S ◽

Radiation Research

ArgumentThis paper brings together the history of risk and the history of DNA repair, a biological phenomenon that emerged as a research field in between molecular biology, genetics, and radiation research in the 1960s. The case of xeroderma pigmentosum (XP), an inherited hypersensitivity to UV light and, hence, a disposition to skin cancer will be the starting point to argue that, in the 1970s and 1980s, DNA repair became entangled in the creation of new models of the human body at risk – what is here conceptually referred to as the vulnerability aspect of body history – and new attempts at cancer prevention and enhancement of the body associated with the new flourishing research areas of antimutagenesis and anticarcinogenesis. The aim will be to demonstrate that DNA repair created special attempts at disease prevention: molecular enhancement, seeking to identify means to increase the self-repair abilities of the body at the molecular level. Prevention in this sense meant enhancing the body's ability to cope with the environmental hazards of an already toxic world. This strategy has recently been adopted by the beauty industry, which introduced DNA care as a new target for skin care research and anti-aging formulas.

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Chemically Induced Models of Parkinson’s Disease: History and Perspectives for the Involvement of Ferroptosis

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.581191 ◽

2020 ◽

Vol 14 ◽

Author(s):

Shuheng Wen ◽

Toshihiko Aki ◽

Kana Unuma ◽

Koichi Uemura

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Environmental Factors ◽

Chemical Inducers ◽

Chemical Models ◽

Chemically Induced ◽

History Of ◽

Genetic And Environmental Factors

Ferroptosis is a newly discovered form of necrotic cell death characterized by its dependency on iron and lipid peroxidation. Ferroptosis has attracted much attention recently in the area of neurodegeneration since the involvement of ferroptosis in Parkinson’s disease (PD), a major neurodegenerative disease, has been indicated using animal models. Although PD is associated with both genetic and environmental factors, sporadic forms of PD account for more than 90% of total PD. Following the importance of environmental factors, various neurotoxins are used as chemical inducers of PD both in vivo and in vitro. In contrast to other neurodegenerative diseases such as Alzheimer’s and Huntington’s diseases (AD and HD), many of the characteristics of PD can be reproduced in vivo by the use of specific neurotoxins. Given the indication of ferroptosis in PD pathology, several studies have been conducted to examine whether ferroptosis plays role in the loss of dopaminergic neurons in PD. However, there are still few reports showing an authentic form of ferroptosis in neuronal cells during exposure to the neurotoxins used as PD inducers. In this review article, we summarize the history of the uses of chemicals to create PD models in vivo and in vitro. Besides, we also survey recent reports examining the possible involvement of ferroptosis in chemical models of PD.

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RECONSTRUCTION OF DNA-REPAIR DEFICIENT XERODERMA PIGMENTOSUM SKIN IN VITRO: A MODEL TO STUDY HYPERSENSITIVITY TO UV LIGHT

Photochemistry and Photobiology ◽

10.1562/2004-07-29-ir-250 ◽

2004 ◽

Author(s):

Françoise Bernerd ◽

Daniel Asselineau ◽

Mathilde Frechet ◽

Alain Sarasin ◽

Thierry Magnaldo

Keyword(s):

Dna Repair ◽

Xeroderma Pigmentosum ◽

Uv Light

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Insulinomimetic properties of trace elements and characterization of their in vivo mode of action

Diabetes ◽

10.2337/diabetes.39.10.1243 ◽

1990 ◽

Vol 39 (10) ◽

pp. 1243-1250 ◽

Cited By ~ 16

Author(s):

L. Rossetti ◽

A. Giaccari ◽

E. Klein-Robbenhaar ◽

L. R. Vogel

Keyword(s):

Trace Elements ◽

Mode Of Action

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Female age affects DNA repair gene expression in mouse GV oocytes from stimulated and unstimulated cycles and in MII oocytes matured in-vivo and in-vitro

10.26226/morressier.5af300ae738ab10027aa9430 ◽

2018 ◽

Author(s):

AR AR ◽

Sally Catt

Keyword(s):

Gene Expression ◽

Dna Repair ◽

Repair Gene ◽

Female Age ◽

Dna Repair Gene ◽

Mouse Gv Oocytes

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Biological NMR Spectroscopy

10.1093/oso/9780195094688.001.0001 ◽

1997 ◽

Keyword(s):

Nuclear Magnetic Resonance ◽

Nmr Spectroscopy ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

State Of The Art ◽

Critical Assessment ◽

Resonance Spectroscopy ◽

History Of ◽

Structure Of Proteins

This book presents a critical assessment of progress on the use of nuclear magnetic resonance spectroscopy to determine the structure of proteins, including brief reviews of the history of the field along with coverage of current clinical and in vivo applications. The book, in honor of Oleg Jardetsky, one of the pioneers of the field, is edited by two of the most highly respected investigators using NMR, and features contributions by most of the leading workers in the field. It will be valued as a landmark publication that presents the state-of-the-art perspectives regarding one of today's most important technologies.

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