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Thermotolerance in Mammalian Systems: A Review
Published in Leopold J. Anghileri, Jacques Robert, Hyperthermia In Cancer Treatment, 2019
Gloria C. Li, Nahid F. Mivechi
Mivechi and Dewey58 measured the level of DNA polymerase alpha and beta in CHO cells during the induction and decay of thermotolerance. Both DNA polymerases show resistance to subsequent heat treatment and there was positive correlation between the level of DNA polymerase beta and cellular survival (Figure 5). These results indicate that the “thermotolerance state” may be a general phenomenon and renders all cellular components, including enzymes, resistant to further heat damage.
Cidofovir and Brincidofovir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Graciela Andrei, Robert Snoeck
The specificity of CDV’s antiviral activity derives in part from a higher affinity of CDVpp for viral DNA polymerases than for host cell polymerases. The inhibitory constant (Ki) of binding affinity of CDVpp for the HCMV DNA polymerase is of 6.6 mM, which is 8–80 times greater than the CDV inhibitory constant for human DNA polymerases (Ki for DNA polymerase-alpha is 51 mM; for DNA polymerase-beta, 520 mM; for DNA polymerase-gamma, 299 mM) (Cherrington et al., 1994; Ho et al., 1992; Xiong et al., 1996). The inhibition constants of CDV for other herpesviruses have also been determined; the Ki values against HSV-1 and HSV-2 polymerases are, respectively, 0.86 and 1.4 mM, providing a selective binding affinity of up to 600-fold for the viral enzymes compared to the human DNA polymerases (Ho et al., 1992).
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Poly(ADP-ribose) polymerases (PARPs) are a group of nuclear enzymes involved in DNA repair and programmed cell death. PARP functions to detect single-stranded DNA breaks and nicks and then signals the downstream enzymes, DNA ligase III, DNA polymerase beta, as well as other scaffolding proteins to initiate repair [44,45]. When the DNA damage cannot be repaired, PARP can also induce apoptosis by signaling mitochondria to release apoptosis inducing factor [46]. PARP inhibitors have been developed to target the DNA repair process in tumors with a high reliance on PARP mediated DNA repair due to homologous recombination defects by increasing double stranded breaks and inducing replication fork collapse in S-phase. These inhibitors have been particularly beneficial in BRCA mutated cancers because of their high reliance on PARP mediated repair [47].
A novel polymerase β inhibitor from phage displayed peptide library augments the anti-tumour effects of temozolomide on colorectal cancer
Published in Journal of Chemotherapy, 2022
Lihong Qin, Mao Huiwen, Jianguo Wang, Yuanyaun Wang, Salman A. Khan, Ying Zhang, Hong Qiu, Longwei Jiang, Lingfeng He, Yan Zhang, Shaochang Jia
DNA polymerase beta (Polβ), a eukaryotic DNA polymerase, is composed of two domains with different enzymatic activity (DNA synthesis and deoxyribose phosphate lyase respectively). These domains are termed as the polymerase and lyase domains respectively, which are critical to the repair of simple base lesions on DNA [22]. The major gap-filling polymerase in short-patch BER is Polβ, which corrects DNA damage from oxidation, deamination and alkylation [23]. Although the Polβ-deleted cells are normal in viability or growth characteristics, they exhibit enhanced sensitivity to DNA-alkylating agents. In patient too, Polβ also was identified as one of the molecules mediating chemotherapy resistance in cancer [24].
An updated patent review of protein arginine N-methyltransferase inhibitors (2019–2022)
Published in Expert Opinion on Therapeutic Patents, 2022
Jinyun Dong, Jilong Duan, Zi Hui, Carmen Garrido, Zhangshuang Deng, Tian Xie, Xiang-Yang Ye
PRMT1 usually catalyzes the asymmetric dimethylation of H4R3 and non-histone proteins such as RNA-binding and DNA-damage repair proteins. Conversely, the activity of PRMT1 is regulated by the phosphorylation at the Y291 site [13]. An up-regulation of PRMT1 expression is frequently observed in cancers of the prostate and bladder, which has a requisite role in suppressing differentiation and promoting cell proliferation. Unlike its relative PRMT1, PRMT2 is less characterized due to its low activity [14]. Despite that, PRMT2 is reported in correlation with tumorigenesis of breast cancer and glioblastoma [3]. PRMT3 has a unique zinc finger domain at the N-terminus that appears to confer its substrate specificity [15]. It catalyzes MMA and ADMA, and the substrates mainly include RNA-binding proteins and sodium channels [12]. The post-translational regulation of PRMT3 is still unclear, but it can be regulated by interacting proteins such as the tumor suppressor DAL-1/4.1B [16]. Overexpression or enhanced activity of PRMT3 has been implicated in cancer, coronary heart disease, and chronic kidney disease [17]. In addition, PRMT3-mediated methylation of hnRNPA1 can enhance gemcitabine drug resistance in pancreatic cancer cells via interaction of ATP binding cassette subfamily G member 2 (ABCG2) [18]. PRMT4 (also known as CARM1) is well known in methylating histones (such as H3R17 and H3R26) and chromatin-associated proteins (such as chromatin remodeling factor BAF155) to regulate transcriptional activation and autophagy [19]. Furthermore, PRMT4 has been involved in diverse cellular and biological functions ranging from splicing, T cell development, adipocyte and muscle cell differentiation, and the maintenance of embryonic stem cell pluripotency [20]. As a coactivator for various cancer-relevant transcription factors, PRMT4 is overexpressed in several types of cancers (such as lung, breast, and glioblastoma) to enhance tumor progression and metastasis [21]. Similar to other PRMTs, the nucleus located PRMT6 methylates both histone and non-histone proteins. It possesses a very distinctive substrate specificity to core histones like H3R2, H4R3, and H2AR3 loci, which are associated with transcriptional repression. Additionally, PRMT6 methylates nonhistone proteins such as DNA polymerase beta (POLB) and HIV-1 proteins Tat, Rev, and NCp7, thereby linking them to DNA base excision during DNA repair and innate cellular immunity, respectively [22]. PRMT8 has a high degree of sequence identity to PRMT1 (~80%), but it has a limited tissue distribution, being mainly restricted to the brain. However, overexpression of PRMT8 can be observed in breast, ovarian, and cervical cancer. It is noteworthy that high levels of PRMT8 are correlated with increased patient survival in breast and ovarian cancer patients, whereas a contrasting situation is observed in gastric cancer patients [23].