title: Defective repair of uracil causes telomere defects in mouse hematopoietic cells.
abstract: Uracil in the genome can result from misincorporation of dUTP instead of dTTP during DNA synthesis, and is primarily removed by uracil DNA glycosylase (UNG) during base excision repair. Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. Using model telomeric DNA substrates, we showed that the position and number of uracil substitutions of thymine in telomeric DNA decreased recognition by the telomere single-strand binding protein, POT1. In primary mouse hematopoietic cells, uracil was detectable at telomeres, and UNG deficiency further increased uracil loads and led to abnormal telomere lengthening. In UNG-deficient cells, the frequencies of sister chromatid exchange and fragility in telomeres also significantly increased in the absence of telomerase. Thus, accumulation of uracil and/or UNG deficiency interferes with telomere maintenance, thereby underscoring the necessity of UNG-initiated base excision repair for the preservation of telomere integrity.
authors.affiliation: From the Laboratory of Molecular Gerontology.
authors.forename: Haritha
authors.initials: H
authors.lastname: Vallabhaneni
authors.affiliation: From the Laboratory of Molecular Gerontology.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Laboratory of Molecular Biology and Immunology, NIA, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Maul
authors.affiliation: From the Laboratory of Molecular Gerontology.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: From the Laboratory of Molecular Gerontology.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Yin
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Department of Medicine, Institute for Research in Immunology and Cancer, University of Montréal, Montréal, Québec H3C 3J7, Canada.
authors.forename: Lea
authors.initials: L
authors.lastname: Harrington
authors.affiliation: Laboratory of Molecular Biology and Immunology, NIA, National Institutes of Health, Baltimore, Maryland 21224, gearhartp@mail.nih.gov.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Gearhart
authors.affiliation: From the Laboratory of Molecular Gerontology, liuyie@mail.nih.gov.
authors.forename: Yie
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D018345:Mice, Knockout; D011485:Protein Binding; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000235:genetics; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D013941:Thymine / Q000378:metabolism; D014498:Uracil / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000172:deficiency / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C507326:POT1 protein, mouse; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D014498:Uracil; D051981:Uracil-DNA Glycosidase; D013941:Thymine
keywords: base excision repair (BER); shelterin; telomerase; telomerase reverse transcriptase (TERT); telomere; uracil DNA glycosylase; uracil misincorporation