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DNA damage induced by topoisomerase inhibitors activates SAMHD 1 and blocks HIV ‐1 infection of macrophages
Author(s) -
Mlcochova Petra,
Caswell Sarah J,
Taylor Ian A,
Towers Greg J,
Gupta Ravindra K
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201796880
Subject(s) - samhd1 , topoisomerase , dephosphorylation , dna damage , biology , cyclin dependent kinase 1 , microbiology and biotechnology , chemistry , dna , cell cycle , phosphorylation , reverse transcriptase , cell , biochemistry , rna , gene , phosphatase
We report that DNA damage induced by topoisomerase inhibitors, including etoposide ( ETO ), results in a potent block to HIV ‐1 infection in human monocyte‐derived macrophages ( MDM ). SAMHD 1 suppresses viral reverse transcription ( RT ) through depletion of cellular dNTP s but is naturally switched off by phosphorylation in a subpopulation of MDM found in a G1‐like state. We report that SAMHD 1 was activated by dephosphorylation following ETO treatment, along with loss of expression of MCM 2 and CDK 1, and reduction in dNTP levels. Suppression of infection occurred after completion of viral DNA synthesis, at the step of 2 LTR circle and provirus formation. The ETO ‐induced block was completely rescued by depletion of SAMHD 1 in MDM . Concordantly, infection by HIV ‐2 and SIV sm encoding the SAMHD 1 antagonist Vpx was insensitive to ETO treatment. The mechanism of DNA damage‐induced blockade of HIV ‐1 infection involved activation of p53, p21, decrease in CDK 1 expression, and SAMHD 1 dephosphorylation. Therefore, topoisomerase inhibitors regulate SAMHD 1 and HIV permissivity at a post‐ RT step, revealing a mechanism by which the HIV ‐1 reservoir may be limited by chemotherapeutic drugs.