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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
A complex network of signaling pathways is altered when cells are exposed to DNA damaging agents [15]. Like other signaling pathways, a DNA damage response (DDR) signaling pathway consists of sensors, transducers, and effectors [16]. DNA damage sensors are the proteins that directly recognize aberrant DNA structures. Mre11-Rad50-Nbs1 (MRN) complex is the key sensor of DNA damage in mammalian cells; it activates ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases, two key transducers of the complex DDR network signaling. Pharmacologic ascorbate activates ATM in a concentration- and time-dependent manner by inducing ATM phosphorylation, and this phosphorylation can be rescued by catalase [4,13]. Following the initial activation, ATM triggers phosphorylation of histone 2Ax (H2Ax), which is a critical event for accumulation of numerous DNA repair proteins and chromatin-remodeling complexes around the DSBs [4,14]. Chk2, another downstream effector of ATM and ART, was also activated by ascorbate treatment [13]. It is also proposed that other downstream targets of ATM and ATR kinases (e.g., BRCA1/2, and p53) [17] are influenced by ascorbate treatment, which are primarily involved in a broad spectrum of cellular processes important for genomic stability and influence cell survival, cell cycle, apoptosis, and senescence [18,19].
Radiotherapy outcomes modeling in the big data era
Published in Jun Deng, Lei Xing, Big Data in Radiation Oncology, 2019
Joseph O. Deasy, Aditya P. Apte, Maria Thor, Jeho Jeong, Aditi Iyer, Jung Hun Oh, Andrew Jackson
Focusing on normal tissue toxicity, van Oorschot et al. (2014) performed ex vivo radiation (1 Gy) of blood lymphocytes from prostate cancer patients. DNA damage repair was quantified via gamma-H2AX foci. They found that the group of patients who experienced less treatment toxicity demonstrated a greater propensity to repair DNA damage, as measured by a lower average ratio of gamma-H2AX foci at 24 h compared with 2 h posttreatment. In a similar study, Beaton et al. (2013) performed ex vivo irradiation on blood lymphocytes (6 Gy) for 10 prostate cancer patients who experienced toxicity and for 20 matched controls. Measurements of the resulting residual chromosome aberrations, such as dicentric chromosomes and excess fragments per cell, where measured. Chromosome aberration levels were much higher in the patient cohort that experienced toxicity. Despite these results, an inherent drawback of methods that use ex vivo irradiation is the expensive and time-consuming nature of the assay. This is perhaps reflected in the overall small number of such studies, and the relatively low patient numbers.
Electromagnetic Emanations from Power Sources and Fixed Specialized Equipment
Published in William J. Rea, EMF Effects from Power Sources and Electrosmog, 2018
Although y-H2AX foci have been used to analyze endogenous and induced DSBs in most studies, recent data have indicated that y-H2AX foci may also be produced by chromatin structure alternations and may not contain DSBs.107–110 Accordingly, some y-H2AX foci may not associate with DNA damage-response proteins such as 53BP1.98,100,101,111 High expression of endogenous y-H2AX in pluripotent mouse embryonic stem cells (−100 large y-H2AX foci per cell) was not explained by DSBs, DNA degradation, or apoptosis, but was attributed to the unusual organization of chromatin in mouse embryonic stem cells.112 The number of endogenous 53BP1 foci (<3 foci/nucleus) appeared normal in mouse embryonic stem cells and is comparable to that found in other cell types.112 In contrast to y-H2AX foci, which may be produced by the DSB-relevant and DSB-unrelated mechanisms, 53BP1 is relocalized to DSBs along with other DNA damage-response proteins, such as phosphorylated ataxia telangiectasia mutated (ATM), Rad50, and meiotic recombination 11 (MRE11), and there is no indication that DSB-unrelated events would result in the formation of the 53BP1 foci.113,114 Therefore, in this study, the researchers analyzed only 53BP1 foci as a more relevant marker for DSBs.
Curcumin induces DNA damage by mediating homologous recombination mechanism in triple negative breast cancer
Published in Nutrition and Cancer, 2020
Gamze Guney Eskiler, Elvan Sahin, Asuman Deveci Ozkan, Ozlem Tugce Cilingir Kaya, Suleyman Kaleli
DNA damage response is regulated by different pathways including base excision repair (BER), mismatch repair (MMR), non-homologous end joining (NHEJ) and homologous recombination (HR)-associated genes such as BRCA1/2, RAD50/51, PALB2, CHEK2, BARD1, BRIP1 etc. The BRCA1 gene plays a crucial role in HR mechanism in response to DNA double-strand breaks (dsDNA). BRCA1 interacts with RAD51 to repair dsDNA breaks and maintain genomic stability and thus, BRCA1 and RAD51 are the main mediator of HR mechanism (9–12). Furthermore, phosphorylation of H2AX (γH2AX) is an important step in recruitment of DNA repair proteins and thus, BRCA1, RAD50, and NBS1 localize with γ-H2AX at sites of DNA damage (13,14). Additionally, DNA breaks are also recognized by poly (ADP-ribose) polymerase 1 (PARP1) and thus PARP1 mediates both DNA repair and cell death (15,16). Therefore, the association H2AX, PARP1, BRCA1, and RAD51 with DNA repair and DNA-damage-induced cell death should be further elucidated.
Effect of epigallocatechin-3-gallate (EGCG) on embryos inseminated with oxidative stress-induced DNA damage sperm
Published in Systems Biology in Reproductive Medicine, 2020
Man Chen, Wanmin Liu, Zhiling Li, Wanfen Xiao
In somatic cells, DNA damage triggers a complex set of responses, including cell cycle arrest, re-localization of DNA repair factors, and apoptosis depending on the severity of DNA damage (Krenning et al. 2019). One of the first cellular responses to DNA damage is the phosphorylation of H2AX at serine 139 located in the unique carboxyl-terminal tail, known as γH2AX (Pouliliou and Koukourakis 2014). This phosphorylation is catalyzed by the members of the phosphatidylinositol 3-kinase (PI3 K)-like family, which is a family of lipid kinases that mediate cellular functions, such as cell growth, proliferation, and DNA repair. The PI3 K-like family includes ataxia telangiectasia mutated (ATM) protein, ATM and Rad3-related (ATR) protein, and DNA protein kinase catalytic subunits (PKcs) (Kuo and Yang 2008). In its inactive form, ATM is sequestered as a dimer or higher-order multimer with the kinase domain bound to a region surrounding serine 1981. DNA damage induces rapid intermolecular auto-phosphorylation of serine 1981, which leads to dimer dissociation and initiation of cellular ATM kinase activity (Bakkenist and Kastan 2003). The activated ATM, a major kinase involved in the phosphorylation of H2AX (Suzuki et al. 2011), activates the effector kinases, checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) through a class of checkpoint factors named checkpoint mediators to initiate the cell cycle checkpoint pathway depending on different types of DNA damage (Sancar et al. 2004). However, there are very few studies that have evaluated DNA damage repair in embryos.
Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Yoojin Song, Sun You Park, Zhexue Wu, Kwang-Hyeon Liu, Young Ho Seo
We next investigated the precise mechanism of action behind the increased DNA-damaging effect of chloram-HDi compared with its parent drug, chlorambucil. Hence, we first treated HL-60 cells with the indicated concentrations of chlorambucil and chloram-HDi for 24 h and measured the expression levels of Rad52, H2AX, γ-H2AX, and β-actin. γ-H2AX is a well- established hallmark of DNA double-strand breaks and Rad52 is an important protein in the homologous recombination repair (HRR) of DNA double-strand breaks43–45. As shown in Figure 5(A), the treatment of cells with chloram-HDi more significantly increased the expression of γ-H2AX than chlorambucil in a dose-dependent manner, indicating that chloram-HDi effectively induced more DNA damage than chlorambucil, which was consistent with the result that we observed in the comet assay. Furthermore, chlrom-HDi downregulated the protein level of Rad52 in a dose-dependent manner. It has been reported that the inhibition of HDACs leads to the reduction of Rad52 protein level. Nevertheless, the reduction of the DNA repair protein, Rad52 contributed to the increased DNA-damaging effect of chloram-HDi, offering a distinct advantage over chlorambucil.