Reversible 5-formyluracil DNA-histone crosslinks: formation and biological effects
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ABSTRACT:
PROVIDER: PRJNA551149 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9602471_1.fastq.gz | Fastqsanger.gz | |||
| SRR9602471_2.fastq.gz | Fastqsanger.gz | |||
| SRR9602472_1.fastq.gz | Fastqsanger.gz | |||
| SRR9602472_2.fastq.gz | Fastqsanger.gz |
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Project description:5-Formyluracil (5fU) is a vital DNA modification that widely presents in cells and organisms. A unique feature of 5fU is the presence of a potentially reactive aldehyde group in its structure, which can realize addition and condensation reactions. However, the biological function details of 5fU are still largely elusive; especially the relationship with protein is still unclear. Herein, we have first showed that 5fU bases have strong affinity with proteins and can yield reversible DNA-protein conjugates with nuclear proteins even under certain spatial space. Besides, 5fU can influence physical properties of nucleosome even chromatin by increasing nucleosome occupancy and stability. What’s more, we firstly confirmed the existence of 5fU-histone crosslinking in thyroid carcinoma tissue by the CHIP of histone H4 combined with LC-MS. These results suggesting the DNA−protein crosslinks (DPC) formation between 5fU and nucleosome core particles may play a potential role in vivo, such as influencing DNA transactions, altering chromatin structure, and stabilizing the nucleosome. In addition, the Schiff base resulted by 5fU may provide us a new direction for capture even quantification of this modification nucleobase based on this condensation reaction with proteins for further epigenetic studies.
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Project description:The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTM). For instance, starvation and low-carbohydrate diets lead to the accumulation of the ketone body, β-hydroxybutyrate (BHB), whose blood concentrations increase more than 10-fold into the millimolar range, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. As with other lysine acylations, Kbhb marks can be removed by histone deacetylases (HDACs). Here, we report that class I HDACs unexpectedly catalyze a reverse reaction that generates the Kbhb modification on target proteins. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and non-canonical HDAC-catalyzed β-hydroxybutyrylation. Based on these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and BHB, thereby generating the amide bond required for covalent attachment of BHB. Also consistent with reversible HDAC activity, Kbhb formation is driven by mass action and substrate availability. This reversible HDAC activity is not limited to BHB but also extends to multiple short-chain fatty acids and represents a novel mechanism of PTM deposition relevant to metabolically-sensitive proteome modifications.
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