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Hormonal Regulation of Cell Proliferation and Differentiation
Published in Jean Morisset, Travis E. Solomon, Growth of the Gastrointestinal Tract: Gastrointestinal Hormones and Growth Factors, 2017
In order for a eukaryotic cell to divide, it has to replicate its genome during the S phase of the cell cycle.1 Several lines of evidence indicate that DNA polymerase alpha is one of the principal enzymes that is involved in the regulation of DNA replication. Thus, aphidicolin, a specific inhibitor of this enzyme, inhibits DNA replication.37 Monoclonal antibodies against the enzyme also inhibit DNA synthesis.38,39 Enhanced activity of the enzyme correlates with enhanced DNA synthesis.40 A cell line that exhibits a temperature-sensitive defect in DNA replication is also a DNA polymerase alpha mutant.41 Although there is a slight increase in the expression of this enzyme prior to the S phase, and a slight decrease through the G2 phase, the enzyme is generally constitutively expressed throughout the cell cycle.42 Nonetheless, the regulation of the expression of this enzyme is believed to occur at the transcriptional level.42 Taken together, these observations indicate that enzymes which are involved in the regulation of cell proliferation are not necessarily active only during a specific phase of the cell cycle and that a variety of intracellular factors probably interact with cell cycle specific enzymes to regulate the exact timing of the proliferative response.
Zidovudine
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
Catherine L. Cherry, Suzanne M. Crowe
Zidovudine activity is not entirely specific to reverse transcriptase because it also has activity against some mammalian DNA polymerases. Inhibition of DNA polymerase alpha and beta is approximately 100-fold less potent than inhibition of reverse transcriptase (Furman et al., 1986; Matthes et al., 1987; König et al., 1989). More substantial inhibition of DNA polymerase delta and epsilon is reported (Nickel et al., 1992). There are no well-established clinical consequences of zidovudine’s inhibition of these cellular enzymes, but some zidovudine has been found incorporated into the DNA of peripheral blood mononuclear cells of patients previously exposed to zidovudine and the cord blood of infants born to HIV-infected women using zidovudine (Olivero et al., 1999; Olivero et al., 2000). Investigators concluded that long-term genotoxicity and/or cytotoxicity may be a possible long-term consequence of therapy with zidovudine (or other NRTI) (Olivero et al., 1999). Zidovudine also causes significant inhibition of DNA polymerase gamma (Konig et al., 1989), which is located in the mitochondrion and responsible for mitochondrial DNA synthesis. Inhibition of mitochondrial DNA synthesis by zidovudine (and other NRTI) is proposed as a mechanism underlying many NRTI-associated toxicities (Lewis and Dalakas, 1995; Brinkman et al., 1998; Brinkman et al., 1999; Kakuda, 2000). In vitro, zidovudine triphosphate inhibits DNA polymerase gamma less efficiently that either stavudine (Lim and Copeland, 2001) or zalcitabine triphosphate (Chen et al., 1991), consistent with the stronger association between stavudine and zalcitabine and side effects attributed to mitochondrial toxicity(Lewis and Dalakas, 1995; Brinkman et al., 1998; Brinkman et al., 1999; Fleischer et al., 2004; see Chapter 229, Stavudine and Chapter 227, Zalcitabine).
Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Algirdas Mikalkėnas, Bazilė Ravoitytė, Daiva Tauraitė, Elena Servienė, Rolandas Meškys, Saulius Serva
A relaxed specificity of an innate polymerase is vital to the survival of the virus3. The ability to control virus proliferation by using compounds that are specific to a replication complex is a tempting and intensively explored approach. A combination of several compounds, reciprocally inhibiting the polymerase, constitutes the essence of the highly active antiretroviral therapy (HAART) – a revolutionary approach ensuring the control over HIV4. This treatment relies on the established allosteric and competitive inhibition modes and resulted inhibition of the polymerase leads to an effective restrain of HIV in vivo5,6. Nucleoside- and nucleotide-based inhibitors of the reverse transcriptase (NRTIs) act either as terminators of viral DNA synthesis or inherent mutagens. Their application often suffers from an insufficient rejection by cellular replicative polymerases, including DNA polymerase alpha, beta and gamma7, thus leading to the high cytotoxicity. Such drawback is addressed by combination of different inhibitors, including non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTI, into one molecule8–10. However, further improvement of polymerase inhibition is restricted by a limited set of compounds and the target enzyme repertoire. In consequence, such compounds have not been translated into any therapeutic agents yet.
Proteome-wide analysis reveals molecular pathways affected by AgNP in a ROS-dependent manner
Published in Nanotoxicology, 2022
Renata Rank Miranda, Anny Carolline Silva Oliveira, Lilian Skytte, Kaare Lund Rasmussen, Frank Kjeldsen
In addition to serine/threonine kinases, we also observed the downregulation of DNA polymerase alpha complex (composed of POLA1 and POLA2 subunits) and DNA topoisomerase 2 A (TOP2A) (Figure 6 and Supplementary Table 7). DNA polymerase alpha complex plays an essential role in DNA synthesis and repair during the mitotic S-phase (Hübscher et al. 2002; Berdis 2017). TOP2A alters DNA structure, enabling DNA repair, replication and transcription processes (Lee and Berger 2019).