Neil3 and NEIL1 DNA glycosylases remove oxidative damages from quadruplex DNA and exhibit preferences for lesions in the telomeric sequence context.
The telomeric DNA of vertebrates consists of d(TTAGGG)n tandem repeats, which can form quadruplex DNA structures in vitro and likely in vivo. Despite the fact that the G-rich telomeric DNA is susceptible to oxidation, few biochemical studies of base excision repair in telomeric DNA and quadruplex structures have been done. Here, we show that telomeric DNA containing thymine glycol (Tg), 8-oxo-7,8-dihydroguanine (8-oxoG), guanidinohydantoin (Gh), or spiroiminodihydantoin (Sp) can form quadruplex DNA structures in vitro. We have tested the base excision activities of five mammalian DNA glycosylases (NEIL1, NEIL2, mNeil3, NTH1, and OGG1) on these lesion-containing quadruplex substrates and found that only mNeil3 had excision activity on Tg in quadruplex DNA and that the glycosylase exhibited a strong preference for Tg in the telomeric sequence context. Although Sp and Gh in quadruplex DNA were good substrates for mNeil3 and NEIL1, none of the glycosylases had activity on quadruplex DNA containing 8-oxoG. In addition, NEIL1 but not mNeil3 showed enhanced glycosylase activity on Gh in the telomeric sequence context. These data suggest that one role for Neil3 and NEIL1 is to repair DNA base damages in telomeres in vivo and that Neil3 and Neil1 may function in quadruplex-mediated cellular events, such as gene regulation via removal of damaged bases from quadruplex DNA.
Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, The University of Vermont, Burlington, Vermont 05405-0068.
Jia
J
Zhou
Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, The University of Vermont, Burlington, Vermont 05405-0068.
Minmin
M
Liu
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112-0850.
Aaron M
AM
Fleming
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112-0850.
Cynthia J
CJ
Burrows
Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, The University of Vermont, Burlington, Vermont 05405-0068. Electronic address: susan.wallace@uvm.edu.
Susan S
SS
Wallace
D000818:Animals; D045647:DNA Glycosylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054856:G-Quadruplexes; D006151:Guanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009699:N-Glycosyl Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D016615:Telomere / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D006151:Guanosine; C046215:8-hydroxyguanosine; D004706:Endodeoxyribonucleases; C540052:NEIL3 protein, mouse; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C473634:NEIL1 protein, human; C468764:NEIL3 protein, human; C481347:Neil1 protein, mouse; C479058:oxoguanine glycosylase 1, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C473642:NEIL2 protein, human
Base Excision Repair; DNA Damage; DNA Glycosylases; DNA Repair; DNA Structure; NEIL1; Neil3; Quadruplex; Sequence Context; Telomeres