Cytoplasmic p53 contributes to the removal of uracils misincorporated by HIV-1 reverse transcriptase

Yossi Saragani, Amnon Hizi, Galia Rahav, Sara Zaouch, Mary Bakhanashvili

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

HIV-1 reverse transcriptase (RT) in the cytoplasm of HIV-infected cells efficiently inserts the non-canonical dUTP into the proviral DNA, and extends the dU-terminated DNA. The misincorporation of dUTP leads to mutagenesis, and uracils can down-regulate viral gene expression. However, uracilation might also protect HIV DNA from auto-integration in the cytoplasm. Tumor suppressor p53 protein, exhibiting inherent 3′→5′ exonuclease activity, provides a potential host-derived repair mechanism during HIV reverse transcription for the misincorporation of various wrong nucleotides, leading to both base-base mismatches and incorporated non-canonical ribonucleotides. Since the presence of proofreading activity is essential for DNA synthesis accuracy, we elucidated the potential involvement of cytoplasmic p53 in the U-editing activities during insertion of dUTP into DNA by recombinant HIV-1 RT (using isogenic p53-proficient and -deficient HCT116 cells). The biochemical data show that p53 in cytoplasm can participate through the intermolecular pathway in a dU-damage-associated repair mechanism by its ability to remove preformed 3′-terminal dUs, thus preventing further extension of 3′ dU-terminated primer during DNA synthesis by HIV-1 RT. The specific depletion of p53 from cytoplasmic lysates of repair-proficient p53-harboring cells reduced this negative effect. Accordingly, the increased abundance of p53 in nutlin-treated cells correlates with enhanced error-correction functions, namely, removal of incorporated uracil. The data substantiate the significance of p53 as a potential proofreader for removal of non-canonical dUTP from HIV DNA, thus preventing the consequences of dUTP misincorporation in cell-type specific infectivity of HIV.

Original languageEnglish
Pages (from-to)804-810
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume497
Issue number2
DOIs
StatePublished - 4 Mar 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • DNA synthesis
  • Exonuclease
  • HIV-1 RT
  • Mutagenesis
  • Uracil
  • p53

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