DNA modifications repaired by base excision repair are epigenetic

• Published in: DNA repair Vol. 12; no. 12; pp. 1152 - 1158
• Main Authors: Moore, Stephen P.G., Toomire, Kimberly J., Strauss, Phyllis R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2013
• Subjects: Binding Sites; Chromatin; Consensus Sequence; CpG Islands; CREB; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - chemistry; Cyclic AMP Response Element-Binding Protein - metabolism; Cytosine - metabolism; DNA base excision repair; DNA Damage; DNA Methylation; DNA Repair - genetics; DNA–protein interaction; Electrophoretic Mobility Shift Assay; Epigenesis, Genetic; Epigenetics; Guanine - metabolism; Humans; Kinetics; Oxidative Stress; Protein Structure, Tertiary; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Response Elements; Transcription factors; Chromatin; Transcription factors; OGG1; G; CREM; ATF-1, ATF-2; DNA base excision repair; BER; AP; hmU; CREB; THF; APEX1; mC; RNS; CRE; ROS; Epigenetics; AID; DNA–protein interaction; hmC; (hm)C; oxoguanine glycosylase; activation induced deaminase; cyclic AMP response element binding protein 1; reactive oxygen species; human AP endonuclease 1; reactive nitrogen species; cAMP response element modulator; (hm)U; cAMP response element; 8-oxo-7,8-dihydroguanine; hydroxymethylcytosine; tetrahydrofuran; base excision repair; (m)C; abasic; 5-methylcytosine; 5-hydroxylmethyluracil; activating transcription factor-1,-2
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2013.10.002

•Oxidative DNA damage and uracil are repaired by base excision repair (BER).•CREB regulates ∼25% of the eukaryotic transcriptome.•Damage repaired by BER modulates CREB binding both positively and negatively.•Modulation is over 2 orders of magnitude.•BER intermediates are epigenetic for critical transcription factors. CREB controls ∼25% of the mammalian transcriptome. Small changes in binding to its consensus (CRE) sequence are likely to be amplified many fold in initiating transcription. Here we show that DNA lesions repaired by the base excision repair (BER) pathway modulate CREB binding to CRE. We generated Kd values by electrophoretic mobility shift assays using purified human CREB and a 39-mer double-stranded oligonucleotide containing modified or wild-type CRE. CRE contains two guanine residues per strand, one in a CpG islet. Alterations in CRE resulted in positive or negative changes in Kd over two orders of magnitude depending on location and modification. Cytosine methylation or oxidation of both guanines greatly diminished binding; a G/U mispair in the CpG context enhanced binding. Intermediates in the BER pathway at one G residue or the other resulted in reduced binding, depending on the specific location, while there was no change in binding when the single G residue outside of the CpG islet was oxidized. CREB recruits other partners after dimers form on DNA. Only UpG increased DNA.CREB dimer formation. Since oxidation is ongoing and conversion of cytosine to uracil occurs spontaneously or at specific times during differentiation and development, we propose that BER substrates are epigenetic and modulate transcription factor recognition/binding.