Identifying the role of PrimPol in TDF-induced toxicity and implications of its loss of function mutation in an HIV+ patient.

Scientific Reports
Vincent N DuongKaren S Anderson

Abstract

A key component of antiretroviral therapy (ART) for HIV patients is the nucleoside reverse transcriptase inhibitor (NRTI) is tenofovir. Recent reports of tenofovir toxicity in patients taking ART for HIV cannot be explained solely on the basis of off-target inhibition of mitochondrial DNA polymerase gamma (Polγ). PrimPol was discovered as a primase-polymerase localized to the mitochondria with repriming and translesion synthesis capabilities and, therefore, a potential contributor to mitochondrial toxicity. We established a possible role of PrimPol in tenofovir-induced toxicity in vitro and show that tenofovir-diphosphate incorporation by PrimPol is dependent on the n-1 nucleotide. We identified and characterized a PrimPol mutation, D114N, in an HIV+ patient on tenofovir-based ART with mitochondrial toxicity. This mutant form of PrimPol, targeting a catalytic metal ligand, was unable to synthesize primers, likely due to protein instability and weakened DNA binding. We performed cellular respiration and toxicity assays using PrimPol overexpression and shRNA knockdown strains in renal proximal tubular epithelial cells. The PrimPol-knockdown strain was hypersensitive to tenofovir treatment, indicating that PrimPol protects against...Continue Reading

References

Oct 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·V P ChuprinaB R Reid
Jun 13, 2001·Sexually Transmitted Infections·A J White
Aug 30, 2001·The Journal of Biological Chemistry·A A JohnsonK A Johnson
Apr 18, 2002·Antimicrobial Agents and Chemotherapy·Gabriel BirkusBerta Otová
Oct 3, 2003·Chemistry & Biology·Amy C Anderson
Oct 4, 2003·Nature Reviews. Drug Discovery·William LewisWilliam C Copeland
Feb 27, 2004·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Julio S G MontanerMichael V O'Shaughnessy
Jun 8, 2006·Environmental and Molecular Mutagenesis·James J Kohler, William Lewis
Aug 1, 2006·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Frank J PalellaUNKNOWN HIV Outpatient Study Investigators
Aug 22, 2008·American Journal of Physiology. Renal Physiology·Matthias WieserRegina Grillari-Voglauer
Nov 5, 2008·Methods in Molecular Biology·Sean P RyderJames R Williamson
Nov 7, 2008·Methods in Molecular Biology·Joseph E TropeaDavid S Waugh
Mar 11, 2009·Laboratory Investigation; a Journal of Technical Methods and Pathology·James J KohlerWilliam Lewis
Jun 23, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jia-Long Fang, Frederick A Beland
Sep 23, 2009·AIDS·UNKNOWN HIV-CAUSAL CollaborationMiguel A Hernán
Jul 1, 2011·AIDS Research and Treatment·Beatriz Fernandez-FernandezAlberto Ortiz
Sep 21, 2013·Journal of the American Society of Nephrology : JASN·Jérôme TourretCorinne Isnard-Bagnis
Nov 12, 2013·Molecular Cell·Sara García-GómezLuis Blanco
Nov 19, 2013·Nature Structural & Molecular Biology·Silvana MourónJuan Méndez
Nov 26, 2013·Molecular Cell·Julie BianchiAidan J Doherty
Mar 19, 2014·Clinical Pharmacology and Therapeutics·S SelvarajE Paintsil
Apr 1, 2014·Nucleic Acids Research·Benjamin A KeenAidan J Doherty
Sep 30, 2014·Nucleic Acids Research·Benjamin A KeenAidan J Doherty
Oct 14, 2014·Methods in Molecular Biology·John P RooneyJoel N Meyer
Feb 3, 2015·Current Protocols in Protein Science·Kathy Huynh, Carrie L Partch
Dec 3, 2015·Molecular Cell·Davide SchiavoneAidan J Doherty
Mar 2, 2016·Nucleic Acids Research·Bas PilzeckerHeinz Jacobs
Apr 1, 2014·Molecular & Cellular Oncology·Sean G RuddAidan J Doherty
Nov 5, 2016·Frontiers in Bioscience (Landmark Edition)·Rachel Krasich, William C Copeland

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Citations

Nov 13, 2020·Critical Reviews in Biochemistry and Molecular Biology·Stephanie TirmanAlessandro Vindigni
Dec 4, 2021·Science Advances·Laura J BaileyAidan J Doherty

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Methods Mentioned

BETA
Electrophoretic mobility shift
thermal shift
electrophoretic shift
PCR
transfection
scraping

Software Mentioned

GraphPad Prism
PrimPol XF Analyzer
Bio
Wave
Quantity One
PRIMPOL
Rad CFX Manager

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