HIV-1 and HIV-2 exhibit divergent interactions with HLTF and UNG2 DNA repair proteins

Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):E3921-30. doi: 10.1073/pnas.1605023113. Epub 2016 Jun 22.

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.

Keywords: HIV; SAMHD1; Vpr; postreplication DNA repair; restriction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle
  • DNA Glycosylases / metabolism*
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism*
  • Endonucleases / metabolism
  • HEK293 Cells
  • HIV-1 / physiology*
  • HIV-2 / physiology*
  • Humans
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / metabolism
  • Proteomics
  • SAM Domain and HD Domain-Containing Protein 1
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • vpr Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • DNA-Binding Proteins
  • HLTF protein, human
  • IL17RB protein, human
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • vpr Gene Products, Human Immunodeficiency Virus
  • vpr protein, Human immunodeficiency virus 1
  • vpr protein, Human immunodeficiency virus 2
  • Ubiquitin-Protein Ligases
  • Endonucleases
  • MUS81 protein, human
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • CCNO protein, human
  • DNA Glycosylases
  • RAD5 protein, S cerevisiae
  • DNA Helicases
  • Monomeric GTP-Binding Proteins