Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription.
DNA repair in chromatin is subject to topological constraints, suggesting a requirement for chromatin modification and remodeling activities. Thymine DNA glycosylase (TDG) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. We report that TDG associates with transcriptional coactivators CBP and p300 and that the resulting complexes are competent for both the excision step of repair and histone acetylation. Furthermore, TDG stimulates CBP transcriptional activity in transfected cells and reciprocally serves as a substrate for CBP/p300 acetylation. Remarkably, this acetylation triggers release of CBP from DNA ternary complexes and also regulates recruitment of repair endonuclease APE. These observations reveal a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability.
Tini
Marc
M
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. mtini@uwo.ca
Benecke
Arndt
A
Um
Soo-Joong
SJ
Torchia
Joseph
J
Evans
Ronald M
RM
Chambon
Pierre
P
D000107:Acetylation; D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics*; D019556:COS Cells; D002471:Cell Transformation, Neoplastic; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D018899:CpG Islands; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D043224:Deoxyribonuclease (Pyrimidine Dimer); D050881:E1A-Associated p300 Protein; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D017384:Sequence Deletion; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D020798:Two-Hybrid System Techniques
D002843:Chromatin; D006657:Histones; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer)