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

Biochemical and Biophysical Research Communications
Yossi SaraganiM Bakhanashvili

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. ...Continue Reading

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