title: Increased human AP endonuclease 1 level confers protection against the paternal age effect in mice.
abstract: Increased paternal age is associated with a greater risk of producing children with genetic disorders originating from de novo germline mutations. Mice mimic the human condition by displaying an age-associated increase in spontaneous mutant frequency in spermatogenic cells. The observed increase in mutant frequency appears to be associated with a decrease in the DNA repair protein, AP endonuclease 1 (APEX1) and Apex1 heterozygous mice display an accelerated paternal age effect as young adults. In this study, we directly tested if APEX1 over-expression in cell lines and transgenic mice could prevent increases in mutagenesis. Cell lines with ectopic expression of APEX1 had increased APEX1 activity and lower spontaneous and induced mutations in the lacI reporter gene relative to the control. Spermatogenic cells obtained from mice transgenic for human APEX1 displayed increased APEX1 activity, were protected from the age-dependent increase in spontaneous germline mutagenesis, and exhibited increased apoptosis in the spermatogonial cell population. These results directly indicate that increases in APEX1 level confer protection against the murine paternal age effect, thus highlighting the role of APEX1 in preserving reproductive health with increasing age and in protection against genotoxin-induced mutagenesis in somatic cells.
authors.affiliation: Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
authors.forename: Jamila R
authors.initials: JR
authors.lastname: Sanchez
authors.affiliation: Duke Cancer Institute, Duke University, 20 Duke Medicine Circle, Durham, NC 27710, USA.
authors.forename: Traci L
authors.initials: TL
authors.lastname: Reddick
authors.affiliation: Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Perez
authors.affiliation: Cell & Tissue Imaging Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Centonze
authors.affiliation: Department of Radiation Oncology, Houston Methodist Research Institute, 6550 Fannin Street, Houston, TX 77030, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Graduate Center for Toxicology, 1095 V.A. Drive, Lexington, KY 40536, USA.
authors.forename: Tadahide
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Pathology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
authors.forename: C Alex
authors.initials: CA
authors.lastname: McMahan
authors.affiliation: South Texas Veteran's Health Care System, 7400 Merton Minter Blvd., San Antonio, TX 78229, USA; Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA; Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA; Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA. Electronic address: walter@uthscsa.edu.
authors.forename: Christi A
authors.initials: CA
authors.lastname: Walter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000235:genetics*; D010331:Paternal Age; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism / Q000473:pathology
chemical_list: C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APEX1; DNA repair; LacI; Mutagenesis; Paternal Age; Spermatogenesis