Introduction to Cancer
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
There is widespread agreement that cancer is a “genetic” disease resulting from damage to the genomes of cells, thus leading to mutations and loss of function in key proteins involved in the management of cellular stability. DNA damage can result from a number of causes ranging from factors in the environment (e.g., UV radiation from the sun, nuclear radiation, carcinogens in the environment, or diet and viral infections) to preventable factors relating to lifestyle (e.g., tobacco and alcohol use, obesity, and lack of exercise). The mechanism by which DNA in the genome is damaged by some of these factors is discussed in more detail in Section 1.6 and Chapter 5. The relative importance of the different factors leading to cancer deaths has been estimated through various studies, and a summary is shown in Figure 1.4.
Stochastic multi-scale modeling of biological effects induced by ionizing radiation
Issam El Naqa in A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Double-strand breaks, on the other hand, represent a severe class of DNA damage since not only one but both DNA strands are affected; thus, some genetic information as well as the connection of the broken ends may be lost. However, even DSB are repaired quite efficiently; human cells typically repair more than 90% of radiation-induced DSB within a day post irradiation. Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in eukaryotic cells in the G1/G0 cell cycle phase; it aims at restoring the DNA integrity in the absence of information on the original sequence, and as such is prone to errors. Following DNA replication in the S phase, in the G2 phase the sister chromatid can be used as a template for restoring the original sequence in an error-free way by the homologous recombination pathway. Conceptually in between these two pathways is a third one, microhomology-mediated end-joining, which is based on using 5 – 25 bp microhomologous sequences downstream or upstream of the break to align the broken strands and try to restore the original sequence; this pathway operates in the S-phase, and is not free of errors.
Mitochondrial Genome Damage, Dysfunction and Repair
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Presence of novel DNA damage repair pathway is confirmed by analysing the different components of DNA damage repair pathways in the mitochondrial sub cellular fractionation. Other techniques employed were sub cellular localization of fluorescent fusion protein, immune gold labelling combined with electron microscopy and silico techniques. Overall the understanding of DNA damage repair systems in mitochondria emerged through successive stages. From the preliminary concept of no repair system to recent discoveries of different robust DNA damage repair pathways such as Base excision repair (BER), Nucleotide excision repair (NER), mismatch repair (MMR) and double strand break repair systems. Along with all these repair systems, the elimination of pre-mutagenic damaged dNTPs and selective degradation of severely damaged DNA complement the repair system to maintain the mitochondrial genome integrity.
Possible association between DNA repair gene variants and cannabis dependence in a Turkish cohort: a pilot study
Published in Psychiatry and Clinical Psychopharmacology, 2018
Sacide Pehlivan, Ahmet Bulent Yazici, Nazan Aydin, Ayse Feyda Nursal, Selin Kurnaz, Ayca Ongel Atar, Ulgen Sever, Zeliha Kincir, Mustafa Pehlivan, Pınar Cetinay Aydin
DNA damage can be due to exposure to exogenous DNA damaging agents, including tobacco smoke or UV radiation, endogenous sources like oxidative stress originating from the respiratory chain, or it can be caused by a reduction in the repair of normal levels of DNA damage that invariably occurs in our genomes [18]. Failure in DNA repair is another mechanism that can induce DNA damage in general, and in neurodevelopmental disorders. Signs of enhanced oxidative stress and oxidative DNA damage have been found in several tissues of patients with schizophrenia. High levels of oxidative stress and oxidative DNA damage were also seen in autism spectrum disorder patients and in animal models relevant to this condition [18]. Besides, multiple evidence support the role of oxidative and nitrosative stress in the pathophysiology of major depression [19]. Therefore, we hypothesized whether DNA repair gene variants may be a risk factor for SUD. To the best of our knowledge, there is no report on the association between XRCC1 rs25487/XRCC4 rs6869366/XPD rs13181 gene variants and risk of SUD in a Turkish cohort. Our results show a significant association between these variants and risk of cannabis and/or SC dependence.
The effect of 111In radionuclide distance and auger electron energy on direct induction of DNA double-strand breaks: a Monte Carlo study using Geant4 toolkit
Published in International Journal of Radiation Biology, 2018
Behnaz Piroozfar, Gholamreza Raisali, Behrouz Alirezapour, Mohammad Mirzaii
Investigations have shown that low energy Auger electrons with ranges comparable to the diameter of DNA, can be responsible for DNA damage which can lead to cell death if not repaired (Cai et al. 2010; Friedland et al. 2011; Pszona et al. 2012; Alizadeh et al. 2014; Nikjoo et al. 2016). DNA damage is caused by both direct and indirect effects of radiation. According to recent investigation, the direct damage is due to radiation energy deposited directly into the DNA by ionization, excitation or electron resonances (i.e. the formation of transient anions) (Sanche 2002, 2005; Li et al. 2010; Alizadeh et al. 2014, 2015), while the indirect effect is induced by species such as free radicals, cations and anions produced by the primary radiation and secondary electrons that interacted with the environment surrounding the DNA (Alizadeh et al. 2013). Several investigations have been performed to study the importance of direct and indirect effects. Antonovic et al. (2012) have mentioned that according to the studies performed by Ito et al. (2006) and Hirayama et al. (2009) that for high LET particles, the direct induced DSBs are dominant with respect to indirect DSBs.
Combination therapy in advanced urothelial cancer: the role of PARP, HER-2 and mTOR inhibitors
Published in Expert Review of Anticancer Therapy, 2020
Veronica Mollica, Ilaria Maggio, Antonio Lopez-Beltran, Rodolfo Montironi, Alessia Cimadamore, Liang Cheng, Alessandro Rizzo, Francesca Giunchi, Riccardo Schiavina, Michelangelo Fiorentino, Eugenio Brunocilla, Francesco Massari
DDR genes are crucial to maintain genomic stability: DNA repair mechanisms restore DNA damage consequent to exogenous or endogenous genomic insults [26]. When this repair mechanism is normally functioning, damaged nucleotides are repaired, and the cell can continue its normal cell cycle; if DDR genes are altered and repair mechanisms are dysfunctional, DNA remains damaged with consequent genome instability, that is a hallmark of carcinogenesis. Among the mechanisms of DNA damage, there are single- or double-strand breaks, crosslinks, mismatch. Double-strand breaks are the most toxic for DNA and can lead to cell death. Repair mechanisms are base or nucleotide excision repair, mismatch repair, and double-strand breaks repair. The latter consists in homologous recombination repair (HRR) or non-homologous end-joining pathway.
Related Knowledge Centers
- DNA
- Nucleobase
- 8-Oxo-2'-Deoxyguanosine
- Mutation
- DNA Repair
- DNA Damage Theory of Aging
- DNA Replication
- Epigenetics
- G1 Phase
- G2 Phase