Abstract
Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Over 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase (pol) pol λ can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol λ might be involved in the nonhomologous end-joining (NHEJ) recombinational repair pathway of DNA double strand breaks (DSBs). Specific inhibitors of these enzymes hold the potential to be developed into a novel class of antitumoral agents. In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications.
Keywords: DNA double strand breaks (DSB), Leukemias, transcriptional factors, DNA polymerases, Nucleoside Inhibitors, Aryl Diketo Hexenoic Acid, Resveratrol
Current Medicinal Chemistry
Title: Human Terminal Deoxynucleotidyl Transferases as Novel Targets for Anticancer Chemotherapy
Volume: 13 Issue: 20
Author(s): Giovanni Maga and Roberto Di Santo
Affiliation:
Keywords: DNA double strand breaks (DSB), Leukemias, transcriptional factors, DNA polymerases, Nucleoside Inhibitors, Aryl Diketo Hexenoic Acid, Resveratrol
Abstract: Mammalian terminal deoxyribonucleotidyl transferase (TDT) catalyzes the non-template-directed polymerization of deoxyribonucleoside triphosphates and has a key role in V(D)J recombination during lymphocyte and repertoire development. Over 90% of leukemic cells in acute lymphocytic leukemia and approximately 30% of leukemic cells in the chronic myelogenous leukemia crisis show elevated TDT activity. This finding is connected to a poor prognosis and response to chemotherapy and reduced survival time. On the other hand, recent data indicated that TDT is not the only terminal deoxyribonucleotidyl transferase in mammalian cells. Its close relative, DNA polymerase (pol) pol λ can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol λ might be involved in the nonhomologous end-joining (NHEJ) recombinational repair pathway of DNA double strand breaks (DSBs). Specific inhibitors of these enzymes hold the potential to be developed into a novel class of antitumoral agents. In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications.
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Cite this article as:
Maga Giovanni and Di Santo Roberto, Human Terminal Deoxynucleotidyl Transferases as Novel Targets for Anticancer Chemotherapy, Current Medicinal Chemistry 2006; 13 (20) . https://dx.doi.org/10.2174/092986706777935087
DOI https://dx.doi.org/10.2174/092986706777935087 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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