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CRISPER Gene Therapy Recent Trends and Clinical Applications
Published in Yashwant Pathak, Gene Delivery, 2022
Prachi Pandey, Jayvadan Patel, Samarth Kumar
NHEJ is a natural way of healing the impairment of DNA strands in most organisms. For example, when UV lights injure the DNA strands of the skin cells, our body can use NHEJ to re-join two broken DNA strands so that they can function again. Commonly, such a method is relatively simple and efficient for fixing damages of genes because this fixing procedure does not require a homologous template to repair the DNA. In NHEJ, the Ku protein will integrate with two ends of the broken DNA strands and form a Ku DNA end complex. This Ku DNA end complex will then associate with a DNA-PKcs complex to slice away overhangs of nucleotides close by the end of the two broken strands. Then, with a support from the XLF: XRCC4 DNA ligase IV, the two fragmented ends of DNA strands will join together and re-join each other via ligation (23). Due to the launching of DSB and some nucleotide deletions, during repair, the original DNA sequence is permanently altered after NHEJ.
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
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].
DNA Double Strand Breaks and Chromosomal Aberrations
Published in K. H. Chadwick, 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.
A systematic review comparing allogeneic hematopoietic stem cell transplant to gene therapy in sickle cell disease
Published in Hematology, 2023
Lianne E. Rotin, Auro Viswabandya, Rajat Kumar, Christopher J. Patriquin, Kevin H.M. Kuo
GT is a newer strategy utilizing autologous HSCs. With this approach, ex vivo gene addition or editing techniques are used to reverse the SCD phenotype by inducing expression of anti-sickling β-globin or γ-globin (fetal globin) via silencing or disruption of the fetal globin repressor, BCL11A [5,6]. Current gene addition approaches use lentiviral vectors for ex vivo transduction of patient-derived HSCs with anti-sickling globin genes [5]. Gene editing techniques use endonucleases to induce DNA double-stranded breaks at targeted sites and take advantage of endogenous non-homologous end joining to create insertions or deletions that disrupt the function of the targeted gene (e.g. BCL11A) [5]. Following a myeloablative conditioning regimen similar to that used for HSCT, successful engraftment of modified patient-derived HSCs results in the expression of anti-sickling or fetal globin genes. While gene therapy still carries the risk of conditioning regimen-associated toxicity, the use of autologous over allogeneic HSCs eliminates GVHD risk and the need for HSC donors [3].
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].
Significance of the Wnt canonical pathway in radiotoxicity via oxidative stress of electron beam radiation and its molecular control in mice
Published in International Journal of Radiation Biology, 2023
Shashank Kumar, Eram Fathima, Farhath Khanum, Suttur S. Malini
Ku70 and Ku80 are two proteins responsible for the non-homologous end-joining pathway (NHEJ), which joins DNA double-strand break. In our study, Ku70 mRNA level in [F(6, 14) = 65.228, p < .0001] liver, [F(6, 14) = 48.70, p < .0001] kidney, [F(6, 14) = 26.254, p < .0001] spleen, [F(6, 14) = 12.448, p < .0001] germ cells, decreased significantly (2- to 5.8-fold) at 24 h post-radiation period (Figure 4(A), Table 3, Figures S3(A–D)). The mRNA level of Ku70 was improved (2- to 3-fold) during the post-radiation period of 30 days except in germ cells, indicating a poor recovery in the mechanism for repairing DNA in germ cells. In addition, damage to renal and hepatic irradiated cells was investigated with a DNA ladder (Figure 4(B)), with severe DNA damage at all doses over the post-24-h irradiation periods. Furthermore, the XRCC6 protein level was significantly decreased in germ cells confirming the failure of the Ku70 mechanism (Figure 6(B)).