Abstract
SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate. In CD4+ myeloid lineage and resting T-cells, SAMHD1 blocks HIV-1 and other viral infections by depletion of the dNTP pool to a level that cannot support replication. SAMHD1 mutations are associated with the autoimmune disease Aicardi–Goutières syndrome and hypermutated cancers. Furthermore, SAMHD1 sensitises cancer cells to nucleoside-analogue anti-cancer therapies and is linked with DNA repair and suppression of the interferon response to cytosolic nucleic acids. Nevertheless, despite its requirement in these processes, the fundamental mechanism of SAMHD1-catalysed dNTP hydrolysis remained unknown. Here, we present structural and enzymological data showing that SAMHD1 utilises an active site, bi-metallic iron-magnesium centre that positions a hydroxide nucleophile in-line with the Pα-O5′ bond to catalyse phosphoester bond hydrolysis. This precise molecular mechanism for SAMHD1 catalysis, reveals how SAMHD1 down-regulates cellular dNTP and modulates the efficacy of nucleoside-based anti-cancer and anti-viral therapies.
Highlights
SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate
These analogues are modified at the bridging α,β-oxygen atom that is in close proximity to the Pα-O5′ phosphoester bond that is cleaved by SAMHD1 in the triphosphohydrolysis reaction
We sought to determine: (i) how a substrate dNTP is coordinated at the catalytic site; and (ii) how SAMHD1 catalyses dNTP triphosphohydrolysis
Summary
SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate. We present structural and enzymological data showing that SAMHD1 utilises an active site, bimetallic iron-magnesium centre that positions a hydroxide nucleophile in-line with the Pα-O5′ bond to catalyse phosphoester bond hydrolysis This precise molecular mechanism for SAMHD1 catalysis, reveals how SAMHD1 down-regulates cellular dNTP and modulates the efficacy of nucleoside-based anti-cancer and anti-viral therapies. HIV-1 and other retroviruses replicate poorly in terminally differentiated cells of the myeloid lineage and resting T-cells[6,7,8,9,10,11,12] This is a result of SAMHD1-dNTP triphosphohydrolase activity that blocks early stage infection through depletion of the dNTP pool to a level that cannot support viral reverse transcription[13,14,15,16]. A role for SAMHD1 in the regulation of DNA repair at stalled replication forks and the suppression of the interferon response by cytosolic nucleic acids has been proposed[40,41]
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