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DNA Damage Repaired by the Base Excision Repair Pathway Is Epigenetic
Author(s) -
Strauss Phyllis R,
Toomire Kim,
Moore Stephen P.G.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.969.2
Subject(s) - creb , oligonucleotide , creb1 , electrophoretic mobility shift assay , dna , microbiology and biotechnology , transcription factor , transcription (linguistics) , biology , dna binding protein , binding site , chemistry , biochemistry , gene , linguistics , philosophy
Many of the enzymes involved in BER are embryonic lethals and at least one (AP endonuclease1) controls protein levels of the critical transcription factor Creb1. We examined whether alterations in the Creb1 consensus sequence repaired by BER affect Creb binding to DNA, using purified Creb1 and a 39‐mer oligonucleotide containing the Creb consensus sequence. Kd values, measured by electrophoretic mobility shift assay, were obtained for unmodified ds oligonucleotide and for one where one or more residues in the consensus sequence were replaced by U or T, 8‐oxoguanine (oxoG) or intermediates in the BER pathway on either upper or lower strand. Conversion of one G residue to oxoG but not the other enhanced recognition by Creb. A U residue opposite one G residue markedly enhanced Creb binding even more than replacement with oxoG but insertion opposite the other markedly decreased binding. Replacement of selected residues with various intermediates in the BER pathway or a T residue interfered with Creb binding. Only one alteration completely prevented dimerization. Since Creb recruits its binding partners as a dimer, this alteration abolishes Creb function. We conclude that DNA modifications repaired by BER control transcription factor binding and constitute a hitherto unrecognized source of epigenetic modulation. *Supported by the G. Harold and Leila Y. Mathers Charitable Foundation and Northeastern University.