@article{1299948,

title = {Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300},

author = {Ryan A Henry and Pietro Mancuso and Yin-Ming Kuo and Rossella Tricarico and Marc Tini and Philip A Cole and Alfonso Bellacosa and Andrew J Andrews},

doi = {10.1021/acs.biochem.6b00841},

issn = {1520-4995},

year  = {2016},

date = {2016-12-01},

journal = {Biochemistry},

volume = {55},

number = {49},

pages = {6766-6775},

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.},

keywords = {Acetylation, Animals, Cell Line, Cells, Cultured, DNA Repair, E1A-Associated p300 Protein, Histones, Knockout, Mice, Thymine DNA Glycosylase},

pubstate = {published},

tppubtype = {article}

}

@article{1299961,

title = {An Fc-Small Molecule Conjugate for Targeted Inhibition of the Adenosine 2A Receptor},

author = {Po-Yuan Hsiao and Jay H Kalin and Im-Hong Sun and Mohammed N Amin and Ying-Chun Lo and Meng-Jung Chiang and John Giddens and Polina Sysa-Shah and Kathleen Gabrielson and Lai-Xi Wang and Jonathan D Powell and Philip A Cole},

doi = {10.1002/cbic.201600337},

issn = {1439-7633},

journal = {Chembiochem},

volume = {17},

number = {20},

pages = {1951-1960},

abstract = {The adenosine A2A receptor (A2A R) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A2A R have the potential for stimulating immune response, which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small molecule A2A R antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and the potential for systemic toxicity due to A2A R effects in the brain and the heart. In this study, we designed an analogue of ZM and tethered it to the Fc domain of the immunoglobulin IgG3 by using expressed protein ligation. The resulting protein-small molecule conjugate, Fc-ZM, retained high affinity for two Fc receptors: FcγRI and the neonatal Fc receptor, FcRn. In addition, Fc-ZM was a potent A2A R antagonist, as measured by a cell-based cAMP assay. Cell-based assays also revealed that Fc-ZM could stimulate interferon γ production in splenocytes in a fashion that was dependent on the presence of A2A R. We found that Fc-ZM, compared with the small molecule ZM, was a superior A2A R antagonist in mice, consistent with the possibility that Fc attachment can improve pharmacokinetic and/or pharmacodynamic properties of the small molecule.},

keywords = {Adenosine A2 Receptor Antagonists, Adenosine A2A, Animals, Female, Humans, Immunoglobulin Fab Fragments, Inbred C57BL, Knockout, Male, Mice, Models, Molecular, Molecular Structure, Receptor, Respiratory Tract Infections, Triazines, Triazoles, Vaccinia virus},

pubstate = {published},

tppubtype = {article}

}

@article{1624367,

title = {HDAC2 targeting stabilizes the CoREST complex in renal tubular cells and protects against renal ischemia/reperfusion injury},

author = {David D Aufhauser and Paul Hernandez and Seth J Concors and Ciaran O’Brien and Zhonglin Wang and Douglas R Murken and Arabinda Samanta and Ulf H Beier and Lauren Krumeich and Tricia R Bhatti and Yanfeng Wang and Guanghui Ge and Liqing Wang and Shayan Cheraghlou and Florence F Wagner and Edward B Holson and Jay H Kalin and Philip A Cole and Wayne W Hancock and Matthew H Levine},

doi = {10.1038/s41598-021-88242-3},

issn = {2045-2322},

journal = {Sci Rep},

volume = {11},

number = {1},

pages = {9018},

abstract = {Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.},

keywords = {Animals, Co-Repressor Proteins, Endothelins, Enzyme Inhibitors, Female, Gene Deletion, Histone Deacetylase 1, Histone Deacetylase 2, Isoenzymes, Kidney Tubules, Knockout, Male, Mice, Proximal, Reperfusion Injury},

pubstate = {published},

tppubtype = {article}

}