Journal
ACS CHEMICAL BIOLOGY
Volume 16, Issue 11, Pages 2560-2569Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00614
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Funding
- National Science Foundation of China (NSFC) [21778062, 92053106]
- Science and Technology Commission of Shanghai Municipality, China [18431907100]
- ShanghaiTech University
- Analytical Instrumentation Center at ShanghaiTech University [SPSTAIC10112914]
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This study presents a novel approach to genetically encode benzoyllysine and fluorinated benzoyllysines into full-length histone proteins in a site-specific manner in live cells. The incorporated unnatural amino acids allow for versatile probes to investigate histone benzoylation under biological environments, providing multiple signals such as F-19 NMR spectra with chemical clarity and fluorescence signals.
Histone posttranslational modifications (PTMs) are vital epigenetic regulators in many fundamental cell signaling pathways and diverse biological processes. Histone lysine benzoylation is a recently identified epigenetic mark associated with active transcription; however, it remains to be explored. Herein, we first report the genetic encoding of benzoyllysine and fluorinated benzoyllysines into full-length histone proteins in a site-specific manner in live cells, based on our rationally designed synthetase and fine-integrated fluorine element into benzoyllysines. The incorporated unnatural amino acids integrating unique features were demonstrated as versatile probes for investigating histone benzoylation under biological environments, conferring multiplex signals such as F-19 NMR spectra with chemical clarity and fluorescence signals for benzoylation. Moreover, the site specifically incorporated lysine benzoylation within native full-length histone proteins revealed distinct dynamics of debenzoylation in the presence of debenzoylase sirtuin 2 (SIRT2). Our developed strategy for genetic encoding of benzoyllysines offers a general and novel approach to gain insights into interactions of site-specific histone benzoylation modifications with interactomes and molecular mechanisms in physiological settings, which could not be accessible with fragment histone peptides. This versatile chemical tool enables a direct and new avenue to explore benzoylation, interactions, and histone epigenetics, which will provide broad utilities in chemical biology, protein science, and basic biology research.
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