Abstract

Elevated intracellular levels of dNTPs have been shown to be a biochemical marker of cancer cells. Recently, a series of mutations in the multifunctional dNTP triphosphohydrolase (dNTPase), sterile alpha motif and histidine–aspartate domain–containing protein 1 (SAMHD1), have been reported in various cancers. Here, we investigated the structure and functions of SAMHD1 R366C/H mutants, found in colon cancer and leukemia. Unlike many other cancer-specific mutations, the SAMHD1 R366 mutations do not alter cellular protein levels of the enzyme. However, R366C/H mutant proteins exhibit a loss of dNTPase activity, and their X-ray structures demonstrate the absence of dGTP substrate in their active site, likely because of a loss of interaction with the γ-phosphate of the substrate. The R366C/H mutants failed to reduce intracellular dNTP levels and restrict HIV-1 replication, functions of SAMHD1 that are dependent on the ability of the enzyme to hydrolyze dNTPs. However, these mutants retain dNTPase-independent functions, including mediating dsDNA break repair, interacting with CtIP and cyclin A2, and suppressing innate immune responses. Finally, SAMHD1 degradation in human primary-activated/dividing CD4+ T cells further elevates cellular dNTP levels. This study suggests that the loss of SAMHD1 dNTPase activity induced by R366 mutations can mechanistically contribute to the elevated dNTP levels commonly found in cancer cells.

Highlights

  • Sterile alpha motif (SAM) and histidine–aspartate (HD) domain–containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that hydrolyzes dNTP substrates into their deoxynucleoside and triphosphate (TP) subparts [1,2,3]

  • Elevated dNTP levels are biochemical markers of cancer cells [36], likely because the uncontrolled cell division observed in these cells requires an abundant dNTP supply. dNTP biosynthesis pathways are extensively investigated, in the field of cancer biology, which led to discovery of various anticancer therapeutics targeting dNTP biosynthesis pathways [59]

  • Recent identification of mutations in SAMHD1 in various cancer cell types generated a unique opportunity to understand the role of dNTP hydrolysis and its regulation in the elevated intracellular dNTP pools observed in cancer cells

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Summary

Introduction

Sterile alpha motif (SAM) and histidine–aspartate (HD) domain–containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase (dNTPase) that hydrolyzes dNTP substrates into their deoxynucleoside and triphosphate (TP) subparts [1,2,3]. This study suggests that SAMHD1 mutations can contribute to the intracellular dNTP level elevation commonly observed in cancer cells.

Results
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