dUTPase: the frequently overlooked enzyme encoded by many retroviruses

Abstract

Retroviruses are among the best studied viruses in last decades due to their pivotal involvement in cellular processes and, most importantly, in causing human diseases, most notably—acquired immunodeficiency syndrome (AIDS) that is triggered by human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2, respectively). Numerous studied were conducted to understand the involvement of the three cardinal retroviral enzymes, reverse transcriptase, integrase and protease, in the life cycle of the viruses. These studies have led to the development of many inhibitors of these enzymes as anti-retroviral specific drugs that are used for routine treatments of HIV/AIDS patients. Interestingly, a fourth virus-encoded enzyme, the deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is also found in several major retroviral groups. The presence and the importance of this enzyme to the life cycle of retroviruses were usually overlooked by most retrovirologists, although the occurrence of dUTPases, particularly in beta-retroviruses and in non-primate retroviruses, is known for more than 20 years. Only more recently, retroviral dUTPases were brought into the limelight and were shown in several cases to be essential for viral replication. Therefore, it is likely that future studies on this enzyme will advance our knowledge to a level that will allow designing novel, specific and potent anti-dUTPase drugs that are effective in combating retroviral diseases. The aim of this review is to give concise background information on dUTPases in general and to summarize the most relevant data on retroviral dUTPases and their involvement in the replication processes and pathogenicity of the viruses, as well as in possibly-associated human diseases.

Comparative Functional Genomic Analysis of Two Vibrio Phages Reveals Complex Metabolic Interactions with the Host Cell

“…This suggests that whereas dUTP pyrophosphatase is absent in V. alginolyticus , lytic Vibrio bacteriophages carry it to possibly satisfy the need for quick uracil hydrolysis, which can interfere during the rolling circle replication if misused by DNA polymerase as a building block. This hypothesis is also supported by the presence of dUTPase in many retroviruses and the enzyme’s role in circumventing the deleterious effects of high uracil presence during the reverse transcription of the viral RNA (Hizi and Herzig, 2015). It is noteworthy that dUTP pyrophosphatase is found in most sequenced bacterial genomes, with Escherichia coli knock-out mutants resulting in accretion of putative short Okazaki fragments and subsequent errors in DNA replication (Tye and Lehman, 1977; Shlomai and Kornberg, 1978), while the T4 phage carries a bifunctional homologous dCTPase-dUTPase gene (gp56), which also takes part in forming 5-hydroxy-methyl-cytosine (Gary et al, 1998).…”

LTR-Retrotransposons from Bdelloid Rotifers Capture Additional ORFs Shared between Highly Diverse Retroelement Types

“…The Dut domain often occurs in vertebrate retroviruses, where it can be variably positioned between gag and RT, between RT and IN, or after IN [28,29]. However, it is rarely found in retrotransposons, and has been reported only in basidiomycetes [30], where it is similarly placed between PR and RT.…”

Distribution, Diversity, and Evolution of Endogenous Retroviruses in Perissodactyl Genomes

“…The significance of the patterns of genomic rearrangement and transcription in the EqERV.U1 lineage remains unclear. However, to the extent that these patterns have been shaped by selection pressures related to the dUTPase gene, they might provide insight into the functions of this poorly understood retroviral enzyme (54).…”