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AFF1 acetylation by p300 temporally inhibits transcription during genotoxic stress response.

Authors
  • Kumari, Nidhi1
  • Hassan, M Abul1
  • Lu, Xiangdong2
  • Roeder, Robert G3
  • Biswas, Debabrata4
  • 1 Laboratory of Transcription Biology, Molecular Genetics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), Kolkata 700032, India. , (India)
  • 2 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065.
  • 3 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065 [email protected] [email protected]
  • 4 Laboratory of Transcription Biology, Molecular Genetics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), Kolkata 700032, India; [email protected] [email protected] , (India)
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Oct 29, 2019
Volume
116
Issue
44
Pages
22140–22151
Identifiers
DOI: 10.1073/pnas.1907097116
PMID: 31611376
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Soon after exposure to genotoxic reagents, mammalian cells inhibit transcription to prevent collisions with repair machinery and to mount a proper DNA damage response. However, mechanisms underlying early transcriptional inhibition are poorly understood. In this report, we show that site-specific acetylation of super elongation complex (SEC) subunit AFF1 by p300 reduces its interaction with other SEC components and impairs P-TEFb-mediated C-terminal domain phosphorylation of RNA polymerase II both in vitro and in vivo. Reexpression of wild-type AFF1, but not an acetylation mimic mutant, restores SEC component recruitment and target gene expression in AFF1 knockdown cells. Physiologically, we show that, upon genotoxic exposure, p300-mediated AFF1 acetylation is dynamic and strongly correlated with concomitant global down-regulation of transcription-and that this can be reversed by overexpression of an acetylation-defective AFF1 mutant. Therefore, we describe a mechanism of dynamic transcriptional regulation involving p300-mediated acetylation of a key elongation factor during genotoxic stress. Copyright © 2019 the Author(s). Published by PNAS.

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