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Cellular and Immunobiology
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Masood Moghul, Sarah McClelland, Prabhakar Rajan
Ultraviolet radiation damages DNA by causing cyclobutane pyrimidine dimers and 6‒4 photoproducts lesions on the DNA.Alters DNA structure, impeding correct replication and transcription.Lesions are excised with the recognition, removal, and replacement of the damaged DNA—'nucleotide excision repair'.Base excision repair occurs with localised damage (from free radicals).
Cancer: A Genetic Disease
Published in Jeremy R. Jass, Understanding Pathology, 2020
Conceivably mutations could inactivate the very genes that detect and repair mutations in other genes. This would allow mutations in cancer-causing genes to accumulate rapidly, a state of hypermutability. A long-established clinical model for this premise is provided by xeroderma pigmentosum, a rare autosomal dominant condition characterised by defective nucleotide excision repair. Affected individuals are extremely sensitive to ultraviolet light and develop multiple skin tumours at a young age.
Neoplasia
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Ultraviolet irradiation is strongly implicated in the aetiology of skin tumours, especially malignant melanoma, of which >90% of cases can be attributed to exposure. As ultraviolet light is of low energy it does not penetrate deeply and the effects are confined to the skin. Ultraviolet rays induce the formation of pyrimidine dimers, which lead to base-pair substitutions during replication. Abnormalities of DNA-repair systems, e.g. defective nucleotide excision repair in Xeroderma pigmentosum, lead to greatly increased risks of skin cancer.
Molecular radiobiology and the origins of the base excision repair pathway: an historical perspective
Published in International Journal of Radiation Biology, 2023
Molecular radiobiologists determined not only that the Base Excision Repair system repairs the vast majority of radiation-induced DNA damages but because of its efficiency, attempted repair of clustered DNA damages produced by ionizing radiation probably causes the majority of lethal events. Importantly, since the major role for Base Excision Repair turned out to be removal of endogenous damages, it plays an important role in our genome maintenance. In fact, mice nullizygous for Ape1, Pol β, Lig1 and Lig3 are embryonic lethals (Friedberg and Meira 2006; Larsen et al. 2007). Also, polymorphisms in the Base Excision Repair enzymes in humans have been associated with increased risk of cancer and neurodegenerative diseases (for reviews see Nemec et al. 2010; Wallace et al. 2012; Wallace 2014). Thus, Molecular Radiobiology has also ended up playing an important role in human health that is unrelated to radiation, an outcome not even originally predicted by Jack Little.
Clinical value of identifying genes that inhibit hepatocellular carcinomas
Published in Expert Review of Molecular Diagnostics, 2022
Ugo Testa, Elvira Pelosi, Germana Castelli
Alterations of DNA repair genes are frequent in HCC. DNA repair processes are constantly active to limit damage in the DNA structure through several reparative mechanisms implying base excision repair, nucleotide excision repair, mismatch excision repair and homologous recombination. Various gene sets, including checkpoint factors, homologous recombination, mismatch repair, base excision repair, nucleotide excision repair, nonhomologous end-joining and Fanconi anemia; somatic alterations in at least one gene pertaining to DDR pathways are observed in about 20% and 3%, respectively of HCC patients; ATM (6%) and ATR (2.5%) are among the DDR genes most frequently mutated; BRCA1/BRCA2 genes are mutated in about 2.5% of HCC patients [28]. Mezina et al. showed that 11.5% of HCC patients possess pathogenic germline variants: 1.8% with BRCA2, 0.9% with MSH6, 0.9% PMS2, 2.2% FANCA, 1.8% BRIP1 [29]. In another cohort of HCC patients, BRCA2 mutations were observed in about 3% of patients [29]. The presence of DDR gene mutations in HCC patients may have some potential implications for precision treatment.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Human cells routinely encounter thousands of DNA damaging lesions with over 20,000 base modifications and over 50,000 single-strand breaks per day [1]. The sources of this damage can be endogenous via hydrolysis, oxidation, or alkylation, or exogenous due to ionizing radiation, ultraviolet light, or chemical agents. In order to maintain viability, human cells have developed mechanisms to detect DNA damage, temporarily stall the cell cycle, and promote repair of the damage to maintain genomic stability [2–5]. When these mechanisms are defective cells can proceed unchecked through the cell cycle resulting in carcinogenesis. There are five main pathways that promote DNA repair or, if the DNA damage cannot be repaired, signal for cell death. These include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and nonhomologous end joining (NHEJ).