DNA strand breaks and gaps target retroviral intasome binding and integration

Gayan Senavirathne, James London, Anne Gardner, Richard Fishel () and Kristine E. Yoder ()
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Gayan Senavirathne: The Ohio State University College of Medicine
James London: The Ohio State University College of Medicine
Anne Gardner: The Ohio State University College of Medicine
Richard Fishel: The Ohio State University College of Medicine
Kristine E. Yoder: The Ohio State University College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Retrovirus integration into a host genome is essential for productive infections. The integration strand transfer reaction is catalyzed by a nucleoprotein complex (Intasome) containing the viral integrase (IN) and the reverse transcribed (RT) copy DNA (cDNA). Previous studies suggested that DNA target-site recognition limits intasome integration. Using single molecule Förster resonance energy transfer (smFRET), we show prototype foamy virus (PFV) intasomes specifically bind to DNA strand breaks and gaps. These break and gap DNA discontinuities mimic oxidative base excision repair (BER) lesion-processing intermediates that have been shown to affect retrovirus integration in vivo. The increased DNA binding events targeted strand transfer to the break/gap site without inducing substantial intasome conformational changes. The major oxidative BER substrate 8-oxo-guanine as well as a G/T mismatch or +T nucleotide insertion that typically introduce a bend or localized flexibility into the DNA, did not increase intasome binding or targeted integration. These results identify DNA breaks or gaps as modulators of dynamic intasome-target DNA interactions that encourage site-directed integration.

Date: 2023
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DOI: 10.1038/s41467-023-42641-4

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