title: Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor.
abstract: The repair of DNA damage, caused by both endogenous and exogenous sources, is necessary to remove lesions that either miscode or block DNA or RNA polymerases. We propose that damage also must be repaired to maintain sequence-specific DNA-protein interactions. In this paper, we have systematically studied two lesions that interfere with one important DNA landmark, the thymine methyl group. Oxidation of the thymine methyl group in DNA generates 5-hydroxymethyluracil (HmU) whereas the misincorporation of dUMP into DNA generates uracil (U), replacing the methyl group with a hydrogen. Both substitutions are shown to inhibit binding of the AP-1 (c-Jun) transcription factor. The energy cost of the perturbation, approximately 0.4 kcal/mol, is similar in magnitude for both U and HmU substitutions and is additive when multiple substitutions are present. A third lesion, substitution of the central C:G base pair of the AP-1 DNA binding domain with the pro-mutagenic U:G mispair, unexpectedly increases AP-1 binding, allowing the transcription factor to interfere with uracil DNA glycosylase activity. Our results support the hypothesis that an additional role for DNA repair systems is to maintain the integrity of sequence-specific DNA-protein interactions, a role of particular importance in long-lived organisms.
authors.affiliation: Department of Biochemistry and Microbiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Rogstad
authors.forename: Pingfang
authors.initials: P
authors.lastname: Liu
authors.forename: Artur
authors.initials: A
authors.lastname: Burdzy
authors.forename: Susan S
authors.initials: SS
authors.lastname: Lin
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Sowers
mesh_terms: D000225:Adenine / Q000378:metabolism; D020137:Base Pair Mismatch; D001667:Binding, Competitive; D003596:Cytosine / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D009692:Nucleic Acid Heteroduplexes / Q000378:metabolism; D009841:Oligonucleotides / Q000378:metabolism; D010432:Pentoxyl / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013941:Thymine / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D014498:Uracil / Q000378:metabolism; D051981:Uracil-DNA Glycosidase
chemical_list: D004268:DNA-Binding Proteins; D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C008055:5-hydroxymethyluracil; D014498:Uracil; D010432:Pentoxyl; D003596:Cytosine; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D051981:Uracil-DNA Glycosidase; D000225:Adenine; D013941:Thymine