The Deoxynucleoside Triphosphate Triphosphohydrolase Activity of SAMHD1 Protein Contributes to the Mitochondrial DNA Depletion Associated with Genetic Deficiency of Deoxyguanosine Kinase.

The Journal of Biological Chemistry
Elisa FranzolinChiara Rampazzo

Abstract

The dNTP triphosphohydrolase SAMHD1 is a nuclear antiviral host restriction factor limiting HIV-1 infection in macrophages and a major regulator of dNTP concentrations in human cells. In normal human fibroblasts its expression increases during quiescence, contributing to the small dNTP pool sizes of these cells. Down-regulation of SAMHD1 by siRNA expands all four dNTP pools, with dGTP undergoing the largest relative increase. The deoxyguanosine released by SAMHD1 from dGTP can be phosphorylated inside mitochondria by deoxyguanosine kinase (dGK) or degraded in the cytosol by purine nucleoside phosphorylase. Genetic mutations of dGK cause mitochondrial (mt) DNA depletion in noncycling cells and hepato-cerebral mtDNA depletion syndrome in humans. We studied if SAMHD1 and dGK interact in the regulation of the dGTP pool during quiescence employing dGK-mutated skin fibroblasts derived from three unrelated patients. In the presence of SAMHD1 quiescent mutant fibroblasts manifested mt dNTP pool imbalance and mtDNA depletion. When SAMHD1 was silenced by siRNA transfection the composition of the mt dNTP pool approached that of the controls, and mtDNA copy number increased, compensating the depletion to various degrees in the different mu...Continue Reading

Associated Clinical Trials

References

Jan 1, 1988·Annual Review of Biochemistry·P Reichard
Jan 1, 1995·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·T SpasokoukotskajaS Eriksson
Aug 1, 1997·Immunology Today·R Resta, L F Thompson
Apr 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·G A KicskaH L Kaufman
Oct 5, 2002·Cellular and Molecular Life Sciences : CMLS·S ErikssonH Eklund
Aug 30, 2003·The Journal of Biological Chemistry·Vera Bianchi, Jozef Spychala
Oct 2, 2003·Proceedings of the National Academy of Sciences of the United States of America·Giovanna PontarinVera Bianchi
Oct 11, 2003·Biochemical and Biophysical Research Communications·Ann SaadaOrly Elpeleg
Jan 30, 2004·The Journal of Biological Chemistry·Chiara RampazzoVera Bianchi
Mar 24, 2005·Proceedings of the National Academy of Sciences of the United States of America·Shiwei SongChristopher K Mathews
Apr 25, 2006·Biochemical and Biophysical Research Communications·Elisa FranzolinVera Bianchi
Feb 16, 2008·Nucleic Acids Research·Zachary F PursellThomas A Kunkel
Apr 18, 2008·The Journal of Biological Chemistry·Luigi LeanzaVera Bianchi
Aug 30, 2008·Molecular Genetics and Metabolism·Ann Saada
Jan 7, 2009·Journal of Inherited Metabolic Disease·A SpinazzolaM Zeviani
Jan 24, 2009·American Journal of Physiology. Gastrointestinal and Liver Physiology·Rajgopal GovindarajanJashvant D Unadkat
Mar 11, 2009·Mitochondrion·Antonio L AndreuElena García-Arumí
Dec 17, 2009·Nucleic Acids Research·Paola FerraroVera Bianchi
Jun 22, 2010·Mutation Research·Chiara RampazzoVera Bianchi
Jan 9, 2013·The Journal of Biological Chemistry·Miriam FranginiChiara Rampazzo
Feb 1, 2013·The Journal of Biological Chemistry·Natalia BeloglazovaAlexander F Yakunin
Apr 23, 2013·Cell Reports·Alexandra CribierMonsef Benkirane
Jul 17, 2013·Proceedings of the National Academy of Sciences of the United States of America·Elisa FranzolinVera Bianchi
Jul 23, 2013·The EMBO Journal·Jan RehwinkelCaetano Reis e Sousa
Oct 22, 2013·Nature Structural & Molecular Biology·Xiaoyun JiYong Xiong

❮ Previous
Next ❯

Citations

Nov 29, 2015·Cancer Chemotherapy and Pharmacology·Chiara RampazzoLars Petter Jordheim
Dec 3, 2016·Nucleosides, Nucleotides & Nucleic Acids·Liya Wang
Jan 10, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Elisa FranzolinChiara Rampazzo

❮ Previous
Next ❯

Methods Mentioned

BETA
transfection
protein assay
PCR
flow cytometry
transfections

Software Mentioned

GraphPad Prism
ImageJ

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.