Structural and functional characterization explains loss of dNTPase activity of the cancer-specific R366C/H mutant SAMHD1 proteins.

Publication Type:

Journal Article


J Biol Chem, p.101170 (2021)


<p>Elevated intracellular levels of deoxy-nucleotide triphosphates (dNTPs) have been shown to be a biochemical marker of cancer cells. Recently, a series of mutations in the multi-functional dNTPase, 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 due to loss of interaction with 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 double-stranded DNA 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.</p>

SAMHD1(113-626) H206R D207N R366C PDB ID 7LTT. SAMHD1(113-626) H206R D207N R366H PDB ID 7LU5.