title: Repair of oxidative DNA base damage in the host genome influences the HIV integration site sequence preference.
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 5'dRP lyase mutant, rescued HIV infection efficiency to wild type levels; this suggested Polβ DNA synthesis activity is not necessary while 5'dRP 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.
authors: Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Geoffrey R
authors: GR
authors: Bennett
authors: Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Ryan
authors: R
authors: Peters
authors: University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, United States of America.
authors: Xiao-hong
authors: XH
authors: Wang
authors: Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Jeungphill
authors: J
authors: Hanne
authors: Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, United States of America; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
authors: Robert W
authors: RW
authors: Sobol
authors: Department of Physics, The Ohio State University, Columbus, Ohio, United States of America; Department of Chemistry and Biochemistry, Division of Hematology, Department of Internal Medicine, Center for RNA Biology, The Ohio State University, Columbus, Ohio, United States of America.
authors: Ralf
authors: R
authors: Bundschuh
authors: Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America; Department of Physics, The Ohio State University, Columbus, Ohio, United States of America.
authors: Richard
authors: R
authors: Fishel
authors: Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors: Kristine E
authors: KE
authors: Yoder
mesh_terms: D000818:Animals; D001483:Base Sequence; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics* / Q000503:physiopathology*; D006790:Host-Parasite Interactions; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D053586:Virus Internalization
chemical_list: D019951:DNA Polymerase beta