title: Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300.
abstract: How protein-protein interactions regulate and alter histone modifications is a major unanswered question in epigenetics. The histone acetyltransferase p300 binds thymine DNA glycosylase (TDG); utilizing mass spectrometry to measure site-specific changes in histone acetylation, we found that the absence of TDG in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation. We demonstrate that TDG interacts with the CH3 domain of p300 to allosterically promote p300 activity to specific lysines on histone H3 (K18 and K23). However, when TDG concentrations approach those of histones, TDG acts as a competitive inhibitor of p300 histone acetylation. These results suggest a mechanism for how histone acetylation is fine-tuned via interaction with other proteins, while also highlighting a connection between regulators of two important biological processes: histone acetylation and DNA repair/demethylation.
authors.affiliation: Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Henry
authors.affiliation: Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.|Universita' degli Studi di Siena , Siena, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mancuso
authors.affiliation: Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Kuo
authors.affiliation: Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Rossella
authors.initials: R
authors.lastname: Tricarico
authors.affiliation: Department of Microbiology and Immunology, Western University , London, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Tini
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.affiliation: Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellacosa
authors.affiliation: Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Andrews
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004260:DNA Repair; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D044502:Thymine DNA Glycosylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D044502:Thymine DNA Glycosylase