Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor

Daniel K. Rogstad, Pingfang Liu, Artur Burdzy, Susan S. Lin, Lawrence Sowers

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8093-8102
Number of pages10
JournalBiochemistry
Volume41
Issue number25
DOIs
StatePublished - Jun 25 2002
Externally publishedYes

Fingerprint

Transcription Factor AP-1
Transcription Factors
Thymine
DNA
Substitution reactions
Uracil-DNA Glycosidase
Uracil
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Base Pairing
DNA Repair
DNA Damage
Hydrogen
Proteins
Repair
Costs and Cost Analysis
Oxidation
5-hydroxymethyluracil

ASJC Scopus subject areas

  • Biochemistry

Cite this

Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor. / Rogstad, Daniel K.; Liu, Pingfang; Burdzy, Artur; Lin, Susan S.; Sowers, Lawrence.

In: Biochemistry, Vol. 41, No. 25, 25.06.2002, p. 8093-8102.

Research output: Contribution to journalArticle

Rogstad, Daniel K. ; Liu, Pingfang ; Burdzy, Artur ; Lin, Susan S. ; Sowers, Lawrence. / Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor. In: Biochemistry. 2002 ; Vol. 41, No. 25. pp. 8093-8102.
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