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Stochastic multi-scale modeling of biological effects induced by ionizing radiation
Published in Issam El Naqa, A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Werner Friedland, Pavel Kundrat
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.
Cockayne Syndrome and the Aging Process
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
In cases of DNA double-strand breaks (DSB), there are other repair systems: Nonhomologous end joining (NHEJ)Microhomology-mediated end joining (MMEJ)Homologous recombination (HR)
Ex vivo gene therapy for lysosomal storage disorders: future perspectives
Published in Expert Opinion on Biological Therapy, 2023
Edina Poletto, Andrew Oliveira Silva, Ricardo Weinlich, Priscila Keiko Matsumoto Martin, Davi Coe Torres, Roberto Giugliani, Guilherme Baldo
The discovery of Zinc Finger Nucleases (ZFNs) in the 1980s was an important step toward developing new ways to actively manipulate the DNA [17]. Scientists realized that they could design zinc-finger domains, which recognize a specific sequence of three base pairs, fused with an endonuclease FokI to act as a molecular scissor. After finding its target, such tools create double‐stranded breaks (DSBs) leading to the activation of two major cellular DNA damage repair pathways in eukaryotic cells. The first is composed of canonical non-homologous end-joining (c-NHEJ) and microhomology-mediated end-joining (MMEJ), and they introduce insertions or deletions (indels) with high efficiency and predictability, potentially leading to gene disruption. Homology-directed repair (HDR) might occur as a second and less efficient pathway, once a donor DNA template is added. It relies on dividing cells and is employed to install targeted mutations or to knock in exogenous DNA sequences [18].
A mechanistic overview of spinal cord injury, oxidative DNA damage repair and neuroprotective therapies
Published in International Journal of Neuroscience, 2023
Jaspreet Kaur, Aditya Mojumdar
Cells have evolved various DNA repair mechanisms to counteract the effects of various types of lesions (Figure 2). Among others, double-strand breaks (DSB) are the most deleterious forms of damage and to repair such damages there are two canonical pathways Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) [82]. NHEJ mediates the direct ligation of DNA ends without the requirement for a homologous template and is not restricted to a particular phase of the cell cycle. In contrast, HR-mediated repair only occurs in S and G2 and requires several crucial and complex steps [83,84]. To maintain the efficiency of the repair, several factors play a role in the DNA repair pathway choice [85]. Other than these two conventional double-strand break repair pathways there are alternative pathways such as micro-homology mediated end-joining (MMEJ) and single-strand annealing (SSA). MMEJ is achieved by a minimal end processing to produce cohesive ends followed by ligation, whereas SSA pathway involves end resection to produce single-stranded DNA ends which subsequently anneal and the resulting strands are ligated [86–88].
Layer-by-Layer technique as a versatile tool for gene delivery applications
Published in Expert Opinion on Drug Delivery, 2021
Dmitrii S. Linnik, Yana V. Tarakanchikova, Mikhail V. Zyuzin, Kirill V. Lepik, Joeri L. Aerts, Gleb Sukhorukov, Alexander S. Timin
Delivery of genome-editing (GE) tools via non-viral carriers has become a widely studied research topic. LbL technology can promote nucleic acid delivery methods that can be used for non-viral delivery of genome-editing tools. One of the most promising GE methods is CRISPR/Cas9, for which Jennifer Doudna and Emmanuelle Charpentier recently received the Nobel prize. The Cas9 nuclease is targeted to a specific site in DNA with the help of a guide RNA (gRNA) sequence. Cas9 then makes a double-strand break (DSB) at the intended site, which is followed by the activation of DSB repair systems. The induced break can be repaired by non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), homology-mediated end joining (HMEJ), or homologous recombination (HR). Reparation of a double-strand break in targeted genes can result in deletions, insertions, or point mutations.