Abstract
BackgroundInosine triphosphate pyrophosphohydrolase (ITPase) is a ‘house-cleaning’ enzyme that degrades non-canonical (‘rogue’) nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We hypothesised that reduced ITPase activity may cause acquired mitochondrial DNA (mtDNA) defects. Furthermore, we investigated whether accumulating mtDNA defects may then be a risk factor for cell transformation, in adult haematological malignancy (AHM).MethodsDNA was extracted from peripheral blood and bone marrow samples. Microarray-based sequencing of mtDNA was performed on 13 AHM patients confirmed as carrying the ITPA 94C>A mutation causing low ITPase activity, and 4 AHM patients with wildtype ITPA. The frequencies of ITPA 94C>A and IVS2+21A>C polymorphisms were studied from 85 available AHM patients.ResultsITPA 94C>A was associated with a significant increase in total heteroplasmic/homoplasmic mtDNA mutations (p<0.009) compared with wildtype ITPA, following exclusion of haplogroup variants. This suggested that low ITPase activity may induce mitochondrial abnormalities. Compared to the normal population, frequencies for the 94C>A and IVS2+21A>C mutant alleles among the AHM patients were higher for myelodyplastic syndrome (MDS) - but below significance; were approximately equivalent for chronic lymphoblastic leukemia; and were lower for acute myeloid leukemia.ConclusionsThis study invokes a new paradigm for the evolution of MDS, where nucleotide imbalances produced by defects in ‘house-cleaning’ genes may induce mitochondrial dysfunction, compromising cell integrity. It supports recent studies which point towards an important role for ITPase in cellular surveillance of rogue nucleotides.
Highlights
During purine nucleotide synthesis in cells, the noncanonical nucleotide inosine triphosphate (ITP) can be synthesized from inosine monophosphate (IMP) by the sequential actions of monophosphate kinase and nucleoside diphosphate kinase
Inosine triphosphate pyrophosphohydrolase (ITPase) acts as a house-cleaning enzyme by degrading other ‘rogue’ purine nucleotides in cells, e.g., endogenous deoxy-inosine triphosphate and deoxy-xanthosine triphosphate [2,3,4]
Knockout studies of ITPase in the mouse have shown that deficient mice show severe growth retardation and die before weaning [7], which was attributed to accumulation of mutagenic deoxy-inosine triphosphate (dITP) in cellular deoxy-nucleotide pools [8]
Summary
During purine nucleotide synthesis in cells, the noncanonical nucleotide inosine triphosphate (ITP) can be synthesized from inosine monophosphate (IMP) by the sequential actions of monophosphate kinase and nucleoside diphosphate kinase. ITPase acts as a house-cleaning enzyme by degrading other ‘rogue’ purine nucleotides in cells, e.g., endogenous deoxy-inosine triphosphate (dITP) and deoxy-xanthosine triphosphate (dXTP) [2,3,4]. Further evidence has been provided by a recent in vitro study on human HeLa cells, with a knockdown ITPA gene, which showed that the absence of functional ITPase activity can lead to accumulation of non-canonical nucleotides which may cause DNA damage and cancer [11]. Inosine triphosphate pyrophosphohydrolase (ITPase) is a ‘house-cleaning’ enzyme that degrades noncanonical (‘rogue’) nucleotides. Complete deficiency is fatal in knockout mice, but a mutant polymorphism resulting in low enzyme activity with an accumulation of ITP and other non-canonical nucleotides, appears benign in humans. We investigated whether accumulating mtDNA defects may be a risk factor for cell transformation, in adult haematological malignancy (AHM)
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