Human terminal deoxynucleotidyl transferases as novel targets for anticancer chemotherapy.
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 lambda can synthesize DNA both in a template dependent (DNA polymerase) and template-independent (terminal deoxyribonucleotidyl transferase) fashion. Pol lambda 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.
Di Santo
Roberto
R
Istituto Pasteur-Fondazione Cenci Bolognetti, Dip. di Studi Farmaceutici, Facoltà di Farmacia, Università di Roma La Sapienza, Italy.
Maga
Giovanni
G
D000818:Animals; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D019951:DNA Polymerase beta / Q000187:drug effects / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007938:Leukemia / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary
D004791:Enzyme Inhibitors; D009705:Nucleosides; C415367:DNA polymerase beta2; C407743:DNA polymerase mu; D004253:DNA Nucleotidylexotransferase; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase