DNA Double Strand Breaks and Chromosomal Aberrations
K. H. Chadwick in Understanding Radiation Biology, 2019
Non-homologous end joining derives from the Classical Theory of chromosome aberration formation (Lea and Catcheside 1942) which was developed to explain the linear–quadratic dose–effect relationship found for aberrations. The aberrations could be seen in the microscope to result from two visible chromosome breaks. The linear–quadratic dose–effect relationship was explained by assuming that each break in a chromosome was linearly proportional with radiation dose and that the combination of the two breaks would be linear–quadratic. The Classical Theory of chromosome aberration formation was developed long before anything was known about the DNA backbone structure of chromosomes and before it was known that a chromosome break would be a DNA double strand break. The concept of non-homologous end joining of DNA double strand breaks between two broken chromosomes was conceived to include DNA double strand break repair in the Classical Theory.
Chemical Causes of Cancer
Peter G. Shields in Cancer Risk Assessment, 2005
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.
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Qi Chen, Margreet C.M. Vissers in Cancer and Vitamin C, 2020
After the DDR signaling pathways activate the DNA repair machinery in the cell, DSBs are repaired by two distinct pathways such as homologous recombination (HR) and nonhomologous end joining (NHEJ). HR is the most used mechanism in which genetic material is exchanged between sister chromatids to repair the damaged DNA without loss of nucleotides. During HR, the enzymes Rad51 and Dmc1 catalyze pairing and shuffling of homologous DNA sequences in mammalian cells, leading to precise repair of the damaged sites. This process is enhanced by breast tumor suppressor BRCA1/2 [20]. During NHEJ, broken ends are brought together and rejoined by DNA ligation, generally with the loss of one or more nucleotides at the site of joining; hence, it is an error-prone DNA repair mechanism. The protein Ku heterodimer (Ku70 and Ku80) recognizes DSBs and acts as a scaffold to recruit the other NHEJ factors, such as DNA-PKcs, x-ray cross complementing protein 4, DNA ligase IV, XRCC4-like factor, and aprataxin-and-PNK-like factor, to DSBs to complete the ligation process [21]. Recent data showed that pharmacologic ascorbate suppresses the expression of HR repair proteins including BRCA1, BRCA2, and RAD51, thus leading to HR deficiency and sensitizing the BRCA1/2 wild-type epithelial ovarian cancer cells to PARP inhibition [22]. Meanwhile, in the presence of HR deficiency, pharmacologic ascorbate also impeded the NHEJ pathway, leading to DNA repair deficiency [22].
Role of N-acetyl cysteine and acetyl-l -carnitine combination treatment on DNA-damage-related genes induced by radiation in HEI-OC1 cells
Published in International Journal of Radiation Biology, 2019
Ufuk Düzenli, Zekiye Altun, Yüksel Olgun, Safiye Aktaş, Ayça Pamukoğlu, Hasan Oğuz Çetinayak, Asuman Feda Bayrak, Levent Olgun
Radiation-induced oxidative stress and DNA damage have a crucial role in ototoxicity (Mujica-Mota et al. 2014). Radiation-induced reactive oxygen species (ROS) disrupt the vital activities of the cells and lead to indirect DNA damage in about 70% of radiation applied patients. Radiation-induced DNA damage leads to the activation of DNA repair mechanisms (Han and Yu 2010). Homologous recombination (HR) and non-homologous end joining are the repair mechanisms of double-strand DNA breaks (Raleigh and Haas-Kogan 2013). Double-strand DNA damage often induces apoptosis, whereas single-strand damage can be repaired easily (Iyama and Wilson 2013). Moreover, reactive oxygen and nitrogen species increase the mitochondrial membrane permeability, and increased cytochrome C in cytosol leads to the activation of the caspase system which are the processes of the apoptosis. The activated caspase system was suggested as another mechanism of radiation-induced cochlear cell toxicity (Figure 1; Low et al. 2006; Mujica-Mota et al. 2014).
An introduction to the special issue of IJRB in honor of the extraordinary legacy of Professor John B. “Jack” Little in the radiation sciences
Published in International Journal of Radiation Biology, 2023
Amy Kronenberg, Edouard I. Azzam
These more difficult types of lesions are considered in the subsequent manuscript contributed by Jac Nickoloff and colleagues. Earlier in his career, Jac spent some years at the Laboratory of Radiobiology as a member of the faculty before going westward. In their article, Nickoloff and colleagues review the DNA lesions induced by radiation and focus on the cellular mechanisms that defend against these lesions. Here the focus is on the roles and mechanisms of non-homologous end joining and homologous recombination, both modes of DNA double-strand break repair, and how these pathways operate in normal and cancer cells. They discuss how the choice between these pathways is regulated during the cell cycle and by other factors, and how homologous recombination can be exploited as a target in cancer radiotherapy.
Ionizing radiation does not impair the mechanisms controlling genetic stability during T cell receptor gene rearrangement in mice
Published in International Journal of Radiation Biology, 2018
Serge M. Candéias, Sylwia Kabacik, Ann-Karin Olsen, Dag M. Eide, Dag A. Brede, Simon Bouffler, Christophe Badie
Under normal conditions, DSB-repair mechanisms are especially important in developing lymphocytes, which must complete several rounds of genetic rearrangement initiated by the introduction of programmed DSBs to express their antigenic receptor genes, immunoglobulin in B lymphocytes and T cell receptor in T lymphocytes. These genes are assembled from discrete V, D, and J gene segments dispersed along distinct genetic loci by a cut and paste mechanism known as V(D)J recombination (Lieber et al. 1994; Gellert 2002). During this process, the ataxia telangiectasia mutated (ATM)-dependent DDR checkpoint is activated by the DNA breaks generated by the RAG recombinase, composed of the recombination-activating genes RAG1 and RAG2 (Gellert 2002; Helmink and Sleckman 2012), expressed only in developing lymphocytes. The resulting DNA ends are then ligated by the non-homologous end joining (NHEJ) DNA repair pathway. Thus, in contrast to most somatic cells, where the activation of the DDR/NHEJ pathway is induced only after exposure to a genotoxic stress such as IR, the DDR/NHEJ pathway is constitutively active in developing lymphocytes. Consequently, lymphocytes are a population of choice to study the effects of radiation exposure on the fidelity of some of the mechanisms in charge of maintaining genetic stability.
Related Knowledge Centers
- Chromosomal Translocation
- Homologous Recombination
- Homology Directed Repair
- Saccharomyces Cerevisiae
- Telomere
- Neoplasm
- Sequence Homology
- Sticky & Blunt Ends
- Microhomology-Mediated End Joining
- DNA End Resection