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DNA Double Strand Breaks and Chromosomal Aberrations
Published in K. H. Chadwick, Understanding Radiation Biology, 2019
Figures 4.3 through 4.14 demonstrate that all chromosomal aberrations can be produced by the micro-homology-enabled recombination repair (MHERR) process derived from the Resnick recombination repair of a DNA double strand break. The Resnick recombination repair is an organised enzymatic process by which the cell attempts to repair the radiation-induced double strand break damage, taking advantage of the availability throughout the nuclear chromosomes of multiple regions of micro-homology. Even when the undamaged chromosome is not homologous with the damaged chromosome, the process can lead to the perfect repair of the damaged chromosome. However, this depends on the correct resolution of the Holliday junction which cannot be guaranteed to take place and the repair of DNA double strand breaks will never be 100% perfect. Radiation will always leave evidence of its effect.
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
The DNA repair capacity of eukaryotic cells is maintained by six main eukaryotic repair processes are as follows: (a) nucleotide excision repair (NER) in which a region of DNA including the damaged nucleotide is removed; (b) base excision repair (BER) in which the damaged base and a few adjacent bases are removed by DNA glycosylases such as the alkylpur-ine-DNA-N-glycosylase (APNG); (c) alkylguanine-DNA alkyl transferase (AGAT) repair in which alkylation products on the O6 position of guanine are removed by a repair protein without excision of the base; (d) mismatch repair (MMR) in which an incorrect base misincorporated during DNA replication is edited by an exonuclease; (e) postreplication repair in which gaps in newly replicated DNA created by polymerase bypass are closed; and (f) nonhomologous end-joining (NHEJ) of double-strand breaks or homologous recombination repair (HRR) of double-strand breaks. These processes are mediated by numerous proteins.
Mutagenic Consequences Of Chemical Reaction with DNA
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
In other circumstances it seems likely that the majority of such gaps do not normally lead to mutation. A long-standing observation is that, especially in E. coli strains deficient in excision repair, UV-induced mutations arise according to the square of dose.72 Bridges73 suggested that this indicated the need for two lesions to generate a mutation. If this were so, only a dose-dependent minority of gaps opposite dimers could be substrate for error-prone repair in a normal strain. The concept of inducible error-prone repair allowed an alternative interpretation that the kinetics of mutation indicated a requirement to both induce error-prone repair and provide a substrate for it, although the evidence probably fits this model less readily. Sedgwick75 has proposed a development of Bridge’s hypothesis for excision-deficient bacteria, where the dimers which give rise to mutations are situated close to each other on opposite strands of DNA so that when the DNA is replicated, the gaps in the newly synthesized DNA will overlap. (Figure 3). It will then be impossible for recombination repair to be initiated by a free end pairing with its complementary strand (Figure 2), and unless error-prone repair occurs the double lesion will be lethal. A specific prediction of this model is that error-prone repair should only occur once at any given site. This prediction has been confirmed by Doubleday et al.76 A second prediction is that all UV-induced mutations should arise in the first generation, even though dimers persist indefinitely in excision-deficient bacteria. Doubleday et al.76 showed that although this prediction was fulfilled under some growth conditions, under other conditions, mutations arose over a period much longer than one generation after irradiation. It is, however, possible that DNA replication is stalled temporarily in potentially mutant cells, an extremely difficult thing to test.
Emerging peptide therapeutics for the treatment of ovarian cancer
Published in Expert Opinion on Emerging Drugs, 2023
Ana C. Veneziani, Eduardo Gonzalez-Ochoa, Amit M. Oza
In cells lacking functional homologous recombination repair (HRR), such as those with BRCA mutations, alternative, error-prone pathways, including non-homologous end-joining repair (NHEJ), repair DNA double-strand breaks. This can lead to the accumulation of genomic instability and eventual cancer cell death. Although NHEJ is faster than HRR and primarily occurs during the G1 phase, recent evidence suggests that it also operates throughout the cell cycle [10]. In addition to well-known NHEJ-associated proteins, such as Ku70/80, DNA-PKcs, DNA pol λ/μ, DNA ligase IV-XRCC4, and XLF, newer proteins are implicated in the process. These include PAXX, MRI/CYREN, TARDBP, IFFO1, ERCC6L2, and RNase H2. Among these proteins, MRI/CYREN serves a dual role by stimulating NHEJ during the G1 phase while inhibiting the pathway during the S and G2 phases [10].
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.
Platforms for delivery of macromolecules to sites of DNA double-strand break repair
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Zhen Cao, Deepika Goyal, Steffen E. Meiler, Yunfeng Zhou, William S. Dynan
Other potential applications for 53BP1-based delivery platforms are in the areas of radiation therapy and gene correction. Radiation therapy kills tumor cells in proportion to the number of unrepaired DSBs. Delivery of macromolecular agents that interfere with repair foci assembly, such as a peptide inhibitor, could provide a potential means to sensitize target cells and reduce the radiation dose needed for tumor control. Gene correction is a method to treat genetic disease. It relies on targeted incision of the genome by an engineered nuclease, followed by homologous recombination repair using a donor template with the correct gene sequence. The efficiency of the process is restricted because homologous recombination operates in competition with nonhomologous end joining (NHEJ), which is the default pathway for DSB repair in mammalian cells. Delivery of a therapeutic agent that suppresses nonhomologous end joining in favor of productive homologous recombination repair pathway could provide a way to increase correction frequency to clinically useful levels. In both these examples, 53BP1-based platforms may afford a way to deliver peptides, aptamers, or other therapeutic agents at high local concentrations in the vicinity of the repair complex.