title: HIV-1 and HIV-2 exhibit divergent interactions with HLTF and UNG2 DNA repair proteins.
abstract: HIV replication in nondividing host cells occurs in the presence of high concentrations of noncanonical dUTP, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) cytidine deaminases, and SAMHD1 (a cell cycle-regulated dNTP triphosphohydrolase) dNTPase, which maintains low concentrations of canonical dNTPs in these cells. These conditions favor the introduction of marks of DNA damage into viral cDNA, and thereby prime it for processing by DNA repair enzymes. Accessory protein Vpr, found in all primate lentiviruses, and its HIV-2/simian immunodeficiency virus (SIV) SIVsm paralogue Vpx, hijack the CRL4(DCAF1) E3 ubiquitin ligase to alleviate some of these conditions, but the extent of their interactions with DNA repair proteins has not been thoroughly characterized. Here, we identify HLTF, a postreplication DNA repair helicase, as a common target of HIV-1/SIVcpz Vpr proteins. We show that HIV-1 Vpr reprograms CRL4(DCAF1) E3 to direct HLTF for proteasome-dependent degradation independent from previously reported Vpr interactions with base excision repair enzyme uracil DNA glycosylase (UNG2) and crossover junction endonuclease MUS81, which Vpr also directs for degradation via CRL4(DCAF1) E3. Thus, separate functions of HIV-1 Vpr usurp CRL4(DCAF1) E3 to remove key enzymes in three DNA repair pathways. In contrast, we find that HIV-2 Vpr is unable to efficiently program HLTF or UNG2 for degradation. Our findings reveal complex interactions between HIV-1 and the DNA repair machinery, suggesting that DNA repair plays important roles in the HIV-1 life cycle. The divergent interactions of HIV-1 and HIV-2 with DNA repair enzymes and SAMHD1 imply that these viruses use different strategies to guard their genomes and facilitate their replication in the host.
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, OH 44106;
authors.forename: Kasia
authors.initials: K
authors.lastname: Hrecka
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, OH 44106;
authors.forename: Caili
authors.initials: C
authors.lastname: Hao
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, OH 44106;
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Shun
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, OH 44106;
authors.forename: Sarabpreet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110;
authors.forename: Selene K
authors.initials: SK
authors.lastname: Swanson
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110;
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, OH 44106; jacek.skowronski@case.edu.
authors.forename: Jacek
authors.initials: J
authors.lastname: Skowronski
mesh_terms: D000595:Amino Acid Sequence; D002453:Cell Cycle; D045647:DNA Glycosylases / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D015498:HIV-2 / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D040901:Proteomics; D000076106:SAM Domain and HD Domain-Containing Protein 1; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D053722:Receptors, Interleukin-17
chemical_list: D045647:DNA Glycosylases; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004720:Endonucleases; D020559:Monomeric GTP-Binding Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D054325:vpr Gene Products, Human Immunodeficiency Virus; C100023:HLTF protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17; C514912:vpr protein, Human immunodeficiency virus 1; C514913:vpr protein, Human immunodeficiency virus 2; C498772:MUS81 protein, human; C484280:SAMHD1 protein, human; C492570:CCNO protein, human; C076225:RAD5 protein, S cerevisiae
keywords: HIV; SAMHD1; Vpr; postreplication DNA repair; restriction