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Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor
- Source :
- Biochemistry. 41(25)
- Publication Year :
- 2002
-
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.
- Subjects :
- HMG-box
DNA repair
DNA damage
Base pair
Base Pair Mismatch
Proto-Oncogene Proteins c-jun
Oligonucleotides
Biology
Biochemistry
Binding, Competitive
DNA Glycosylases
Pentoxyl
chemistry.chemical_compound
Cytosine
Humans
Protein–DNA interaction
Uracil
Uracil-DNA Glycosidase
N-Glycosyl Hydrolases
Adenine
Nucleic Acid Heteroduplexes
Molecular biology
DNA-Binding Proteins
Transcription Factor AP-1
chemistry
DNA glycosylase
Uracil-DNA glycosylase
DNA
Thymine
DNA Damage
Protein Binding
Subjects
Details
- ISSN :
- 00062960
- Volume :
- 41
- Issue :
- 25
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....4250850155bc7d00e4bca04c160ec9d9