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Repair of oxidative DNA base damage in the host genome influences the HIV integration site sequence preference

Bennett, GR and Peters, R and Wang, XH and Hanne, J and Sobol, RW and Bundschuh, R and Fishel, R and Yoder, KE (2014) Repair of oxidative DNA base damage in the host genome influences the HIV integration site sequence preference. PLoS ONE, 9 (7).

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Abstract

Host base excision repair (BER) proteins that repair oxidative damage enhance HIV infection. These proteins include the oxidative DNA damage glycosylases 8-oxo-guanine DNA glycosylase (OGG1) and mutY homolog (MYH) as well as DNA polymerase beta (Polβ). While deletion of oxidative BER genes leads to decreased HIV infection and integration efficiency, the mechanism remains unknown. One hypothesis is that BER proteins repair the DNA gapped integration intermediate. An alternative hypothesis considers that the most common oxidative DNA base damages occur on guanines. The subtle consensus sequence preference at HIV integration sites includes multiple G:C base pairs surrounding the points of joining. These observations suggest a role for oxidative BER during integration targeting at the nucleotide level. We examined the hypothesis that BER repairs a gapped integration intermediate by measuring HIV infection efficiency in Polβ null cell lines complemented with active site point mutants of Polβ. A DNA synthesis defective mutant, but not a 59dRP lyase mutant, rescued HIV infection efficiency to wild type levels; this suggeted Polβ DNA synthesis activity is not necessary while 59dRP lyase activity is required for efficient HIV infection. An alternate hypothesis that BER events in the host genome influence HIV integration site selection was examined by sequencing integration sites in OGG1 and MYH null cells. In the absence of these 8-oxo-guanine specific glycosylases the chromatin elements of HIV integration site selection remain the same as in wild type cells. However, the HIV integration site sequence preference at G:C base pairs is altered at several positions in OGG1 and MYH null cells. Inefficient HIV infection in the absence of oxidative BER proteins does not appear related to repair of the gapped integration intermediate; instead oxidative damage repair may participate in HIV integration site preference at the sequence level. © 2014 Bennett et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bennett, GR
Peters, R
Wang, XH
Hanne, J
Sobol, RWrws9@pitt.eduRWS9
Bundschuh, R
Fishel, R
Yoder, KE
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
UNSPECIFIEDSpies, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 22 July 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0103164
Schools and Programs: Graduate School of Public Health > Human Genetics
Refereed: Yes
Date Deposited: 26 Sep 2014 14:31
Last Modified: 05 Feb 2019 16:55
URI: http://d-scholarship.pitt.edu/id/eprint/23010

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