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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].
The Premature Aging Characteristics of RecQ Helicases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Christ Ordookhanian, Taylor N. Dennis, J. Jefferson P. Perry
The physical and functional interactions of WRN with proteins in the DNA repair pathways, such as FEN-1, Ku70/80, RAD52, and PARP-1, strongly indicate key repair roles for WRN that may impact the clinical phenotype of WS. Links to the base excision repair (BER) pathway include physical and functional interactions with multiple BER components that include: replication protein A (RPA) [84], PCNA [85] polδ [86,87], flap endonuclease 1 (FEN-1) [83], polβ [88], and poly(ADP-ribose)polymerase 1 (PARP-1) [80]. A potential link to the nucleotide excision repair (NER) pathway is indicated by the interaction of WRN and XPG [89], while links to DNA DSB repair pathways are perhaps the most numerous. An interaction of WRN with the NHEJ-essential protein kinase DNA–PK that also has capping functions at mammalian telomeres, provided a first link to NHEJ pathway [52,90,91]. WRN is only one of the four known in vivo substrates of DNA–PK, and full-length WRN activity is regulated by both the Ku70/80 subunit and holo–DNA–PK [52,91] and WRN exonuclease activity is stimulated in vitro the DNA–PK subunit Ku70/80 [77,78,91–93]. WRN has been observed in an endogenous complex with the Ku70/80 subunit and poly(ADP-ribose) polymerase-1 (PARP-1) [94] that binds sites of SSBs and DSBs, and is also implicated in the control of genomic integrity and mammalian life span [95]. XRCC4/Ligase IV that functions in NHEJ also stimulates the exonuclease, but not the helicase activity of WRN [78,92]. Interestingly, NHEJ-mediated repair in WS cells displays extensive deletions, which suggests that another, less regulated exonuclease may substitute for WRN in these cells [96].
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
Oxidative stress refers to an imbalance between the generation of free radicals and antioxidant defenses for repair. It has been proposed that oxidative stress plays a role in the pathogenesis of several distinct diseases, and may also be a part of the common pathogenic mechanism in numerous major mental disorders since the brain has relatively more vulnerability to oxidative damage [3]. Numerous studies have searched for the relation between oxidative stress and psychiatric diseases [4,5]; however, few have assessed the possible role of oxidative stress in SUDs. Oxidative stress can induce damage to DNA. Multiple, complementary DNA repair systems have evolved to protect the genome against the harmful effects of DNA lesions [6]. X-ray repair cross-complementing group 1 (XRCC1) is one of the essential genes in the base-excision repair pathway, encodes a protein that plays a role in the repair of DNA single-strand breaks [7]. XRCC4 is found on the chromosomal 5q14.2 and restores DNA double-strand breaks (DSBs) repair. Xeroderma pigmentosum group D (XPD, also referred as ERCC2) encodes a helicase that is a component of the transcription factor TFIIH. This factor is a key member of the nucleotide-excision repair pathway that accounts for influencing repairs to bulky adducts and UV-induced DNA damage [8]. DNA repair gene changes were shown to result in a decrease in DNA repair capacity. Therefore, we hypothesized that the XRCC1 Arg399Gln (rs25487), and XRCC4 G1394 T (rs6869366), and XPD (rs13181) variants play a role in SUD. To test this hypothesis, we aimed to investigate whether functional variants of DNA repair gene might be a risk factor for SUD in a Turkish cohort.
Genotypic analysis of XRCC4 and susceptibility to cervical cancer
Published in British Journal of Biomedical Science, 2020
MK Gupta, AS Kushwah, R Singh, M Banerjee
We hypothesised that any of four Single Nucleotide Polymorphisms (SNPs) of XRCC4 viz. intron3 Deletion/Insertion polymorphism (DIP) (rs28360071), intron7 DIP (rs28360317), G-1394T (rs6869366) and G-652T (rs2075685) are associated with cervical cancer. These polymorphisms are most frequent and subtle genetic variations in the human genome and have great potential for application to association studies in complex diseases.