Three Prime Repair Exonuclease 1 Preferentially Degrades the Integration-incompetent HIV-1 DNA Through Favorable Kinetics, Thermodynamic, Structural and Conformational Properties

Overview

Journal bioRxiv

Date 2024 Apr 2

PMID 38562877

Authors

Prem Prakash

Purva Khodke

Muthukumar Balasubramaniam

Benem-Orom Davids

Thomas Hollis

Jamaine Davis

Jui Pandhare

Bajarang Kumbhar

Chandravanu Dash

Affiliations

Soon will be listed here.

Abstract

HIV-1 integration into the human genome is dependent on 3'-processing of the reverse transcribed viral DNA. Recently, we reported that the cellular Three Prime Repair Exonuclease 1 (TREX1) enhances HIV-1 integration by degrading the unprocessed viral DNA, while the integration-competent 3'-processed DNA remained resistant. Here, we describe the mechanism by which the 3'-processed HIV-1 DNA resists TREX1-mediated degradation. Our kinetic studies revealed that the rate of cleavage () of the 3'-processed DNA was significantly lower than the unprocessed HIV-1 DNA by TREX1. The efficiency of degradation (/K) of the 3'-processed DNA was also significantly lower than the unprocessed DNA. Furthermore, the binding affinity (K) of TREX1 was markedly lower to the 3'-processed DNA compared to the unprocessed DNA. Molecular docking and dynamics studies revealed distinct conformational binding modes of TREX1 with the 3'-processed and unprocessed HIV-1 DNA. Particularly, the unprocessed DNA was favorably positioned in the active site with polar interactions with the catalytic residues of TREX1. Additionally, a stable complex was formed between TREX1 and the unprocessed DNA compared the 3'-processed DNA. These results pinpoint the biochemical mechanism by which TREX1 preferentially degrades the integration-incompetent HIV-1 DNA and reveal the unique structural and conformational properties of the integration-competent 3'-processed HIV-1 DNA.

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