DOI: 10.1073/pnas.95.7.3519. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression

A role for histone deacetylase activity in HDAC1-mediated transcriptional repression

10.1073/pnas.95.7.3519

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Treatment of mammalian cells with small molecule histone deacetylase (HDAC) inhibitors induces changes in the transcription of specific genes. These changes correlate directly with an increase in the acetylation levels of all four core histones in vivo . Antibodies directed against endogenous HDAC1, HDAC2, or HDAC3 immunoprecipitate histone deacetylase activity that is inhibited in vitro by the small molecule trapoxin (TPX), and all three HDACs are retained by a TPX-affinity matrix. HDAC1 and HDAC2 are associated in HeLa cells in a complex that is predominantly separate from an HDAC3 immune complex. Both Jurkat HDAC1 and HeLa HDAC1/2 immune complexes deacetylate all four core histones and recombinant HDAC1 deacetylates free and nucleosomal histones in vitro . Purified recombinant HDAC1 deacetylates core histones in the absence of protein cofactors. Site-directed mutagenesis was used to identify residues required for the enzymatic and structural integrity of HDAC1. Mutation of any one of four conserved residues causes deleterious effects on deacetylase activity and a reduced ability to bind a TPX-affinity matrix. A subset of these mutations also cause a decreased interaction with the HDAC1-associated proteins RbAp48 and mSin3A. Disruption of histone deacetylase activity either by TPX or by direct mutation of a histidine presumed to be in the active site abrogates HDAC1-mediated transcriptional repression of a targeted reporter gene in vivo .

Bibliography

Hassig, C. A., Tong, J. K., Fleischer, T. C., Owa, T., Grable, P. G., Ayer, D. E., & Schreiber, S. L. (1998). A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proceedings of the National Academy of Sciences, 95(7), 3519â3524.

Authors 7

Christian A. Hassig (first)
Jeffrey K. Tong (additional)
Tracey C. Fleischer (additional)
Takashi Owa (additional)
Phyllis G. Grable (additional)
Donald E. Ayer (additional)
Stuart L. Schreiber (additional)

References 22 Referenced 300

10.1016/S0960-9822(06)00042-X
10.1016/S0092-8674(00)80211-1
10.1016/S1367-5931(97)80066-X
10.1038/38664
10.1002/bies.950170510
10.1126/science.272.5260.408
10.1073/pnas.93.25.14503
10.1074/jbc.272.44.28001
10.1073/pnas.93.23.12845
10.1016/S0959-437X(96)80048-7
10.1016/S0092-8674(00)80214-7
10.1021/ja9615841
10.1074/jbc.271.26.15837
, eds F M Ausubel, et al. (Wiley, New York) Current Protocols in Molecular Biology, pp. 10.51–10.55 (1995). / Current Protocols in Molecular Biology by Ausubel F M (1995)
10.1016/0003-9861(89)90170-7
10.1016/S0021-9258(19)52481-4
10.7164/antibiotics.43.1101
10.1016/S0006-291X(88)80997-5
10.1016/0092-8674(95)90355-0
10.1016/S0092-8674(00)80215-9
10.1016/S0092-8674(00)80218-4
10.1126/science.277.5322.88

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:32 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 4:51 p.m.)
Indexed	2 days, 17 hours ago (Sept. 3, 2025, 6:31 a.m.)
Issued	27 years, 5 months ago (March 31, 1998)
Published	27 years, 5 months ago (March 31, 1998)
Published Online	27 years, 5 months ago (March 31, 1998)
Published Print	27 years, 5 months ago (March 31, 1998)

Funders 0

None

BibTeX

@article{Hassig_1998, title={A role for histone deacetylase activity in HDAC1-mediated transcriptional repression}, volume={95}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.95.7.3519}, DOI={10.1073/pnas.95.7.3519}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Hassig, Christian A. and Tong, Jeffrey K. and Fleischer, Tracey C. and Owa, Takashi and Grable, Phyllis G. and Ayer, Donald E. and Schreiber, Stuart L.}, year={1998}, month=mar, pages={3519–3524} }

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