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Mutagenic Consequences Of Chemical Reaction with DNA
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
The right-hand side of Figure 1 shows a more recently discovered variation in which the damaged base is recognized by an N-glycosidase which removes the base, leaving an apurinic (or apyrimidinic) site. Although such sites are alkali-labile and show up as discontinuities in alkaline sucrose gradients, the DNA backbone is intact in vivo. Apurinic sites, which can also form spontaneously, are recognized by an apurinic endonuclease, and the subsequent stages of repair are presumably identical to those of classical excision.18
Genomic DNA damage induced by co-exposure to DNA damaging agents and pulsed magnetic field
Published in International Journal of Radiation Biology, 2023
Beatriz López-Díaz, Silvia Mercado-Sáenz, Antonio M. Burgos-Molina, Alejandro González-Vidal, Francisco Sendra-Portero, Miguel J. Ruiz-Gómez
Other authors reported that sinusoidal MF (5 mT) enhances the apurinic/apyrimidinic site number in human glioma cells exposed to MMS, suggesting an increment in the activity or lengthen of lifetime of radical pairs as a mechanism of action (Koyama et al. 2008). Moreover, Luukkonen et al. (2011) found that 100 μT sinusoidal 50 Hz MF alters the cellular response of neuroblastoma cells to MMS, i.e. increasing its sensitivity to MMS-induced damage. On the other hand, Cho et al. (2007) found that exposure of fibroblasts to 0.8 mT, sinusoidal 60 Hz, MF increases the damage induced by bleomycin to DNA. In addition, Miyakoshi et al. (2012) indicated that the possible mechanism responsible for DNA damage induced by co-exposure of rats to bleomycin and 10 mT 50 Hz MF is related to ROS. Recently, Sanie-Jahromi and Saadat (2017) published that exposures of MCF-7 breast cancer cells to bleomycin in combination with MF (50 Hz, 0.5 mT, intermittent 15/15 min. on/off, 30 min. total exposure) increases the levels of expression of some genes related to DNA repair mechanisms, suggesting an increase in the damage produced by the MF exposure.
Therapeutic Perspective of Temozolomide Resistance in Glioblastoma Treatment
Published in Cancer Investigation, 2021
Qin Xia, Liqun Liu, Yang Li, Pei Zhang, Da Han, Lei Dong
In malignant tumors, the BER system is hyperactive and negatively regulates the MMR system, which contributes to drug resistance. The BER system rapidly recognizes and repairs N-methylated bases, which cannot be recognized by MGMT, and the BER system corrects mispairs recognized by MMR. N-methylpurine DNA glycosylase (MPG) excises DNA alkylated bases in the BER system, and it creates an apurinic/apyrimidinic site (AP-site). The corresponding DNA glycosylase and/or apurinic/apyrimidinic endonuclease (APEX1) will hydrolyze the 5′ (backbone) at the AP-site and ultimately lead to single-strand breaks. Agnihotri et al. built a GSC-like system using GB xenograft models and demonstrated that MPG expression enhanced TMZ resistance compared with cell lines that did not express MPG (31). Therefore, MPG loss increases the sensitivity to TMZ. In addition, poly ADP-ribose polymerase (PARP), which is upregulated in gliomas, repairs DNA single-strand breaks and regulates the BER and MMR pathways (32). Bandey et al. showed that granulin (GRN) precursor upregulated DNA repair (like PARP) and orchestrated tumor stemness to promote TMZ resistance in GB (33). A study by Tentori et al. found that in eight out of ten GSC lines, the combination of PARP1 inhibitors with TMZ increased the anti-tumor effect (34). Besides, non-homologous end joining (NHEJ) and homologous recombination (HR) repair double-strand break indirectly induced by TMZ and likely contribute to chemoresistance in GB (35).
Circadian expression of DNA methylation and demethylation genes in zebrafish gonads
Published in Chronobiology International, 2018
Juan Fernando Paredes, Jose Fernando Lopez-Olmeda, Jose A Muñoz-Cueto, F. Sánchez-Vázquez
In this paper, we investigate the existence of daily rhythms of expression of key genes involved in DNA methylation and demethylation in zebrafish gonads. To this end, we selected three genes that encode proteins involved in de novo methylation processes: DNA methyltransferase (dnmt) 4, dnmt5, and dnmt7 (Kamstra et al. 2014). Dnmts are responsible for the most common covalent modifications of DNA in eukaryotes through the methylation of cytosine, playing a crucial role in the normal development of organisms (Campos et al. 2012; Martin et al. 1999; Mhanni and McGowan 2004). In addition, we selected five key genes involved in DNA demethylation: the 10-11 translocation enzyme (tet2) catalyzes the demethylation process of 5-methylcytosine (5 mC) to 5-hydroxymethyl cytosine (5 hmC), then to 5-formylcytosine (5fC) and next to 5-carboxylcytosine (5caC) in three different steps (Ito et al. 2010). The 5 mC may also follow a deamination route to form thymine by the growth arrest and DNA damage 45 alpha (gadd45aa), the apolipoprotein B-editing catalytic subunit 2b (apobec2b) and the activation-induced cytidine deaminase (AID). The 5hmC can also be deaminated to 5-hydroxymethyl uracil (5 hmU) by a complex that includes the gadd45aa, the AID, and the apobec2b (Williams and Schalinske 2012; Moore et al. 2013). For all three routes, the thymine DNA glycosylase (TDG) catalyzes the final step of demethylation to an unmodified cytosine by means of the base excision repair system (BER) removing the modified base and leaving an apurinic/apyrimidinic site (Zhang et al. 2012). Then, the methyl CpG-binding domain protein 4 (mbd4) and gadd45aa foster the last step toward the formation of unmodified cytosine concomitantly working with TDG when thymine and 5 hmC are to be excised (Niehrs and Schäfer 2012). The apurinic/apyrimidinic site is recognized by the BER system resulting in the replacement of unmodified cytosine. A schematic diagram of the whole process is depicted in Dhliwayo et al. (2014).