Lysine Acetylation and Succinylation in HeLa Cells and their Essential Roles in Response to UV-induced Stress

Xu, Hong; Chen, Xuanyi; Xu, Xin; Shi, Rongyi; Suo, Shasha; Cheng, Kaiying; Zheng, Zhong; Wang, Meixia; Wang, Liangyan; Zhao, Ye; Teng, Bing; Hua, Yuejin

doi:10.1038/srep30212

Cited by 44 publications

(32 citation statements)

References 29 publications

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“…In addition to physiological processes, lysine succinylation is also associated with pathophysiological processes and diseases [ 23 ]. Lysine succinylation is closely correlated with fatty acid metabolism and amino acid metabolism [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

Yuan

Yang

et al. 2020

Clin Epigenet

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Background Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is assembled by histones and non-histones into a chromatin-like cccDNA minichromosome in the nucleus. The cellular histone acetyltransferase GCN5, displaying succinyltransferase activity, is recruited onto cccDNA to modulate HBV transcription in cells. Clinically, IFN-α is able to repress cccDNA. However, the underlying mechanism of IFN-α in the depression of cccDNA mediated by GCN5 is poorly understood. Here, we explored the effect of IFN-α on GCN5-mediated succinylation in the epigenetic regulation of HBV cccDNA minichromosome. Results Succinylation modification of the cccDNA minichromosome has been observed in HBV-infected human liver-chimeric mice and HBV-expressing cell lines. Moreover, histone H3K79 succinylation by GCN5 was identified in the system. Interestingly, the mutant of histone H3K79 efficiently blocked the replication of HBV, and interference with GCN5 resulted in decreased levels of HBV DNA, HBsAg, and HBeAg in the supernatant from de novo HBV-infected HepaRG cells. Consistently, the levels of histone H3K79 succinylation were significantly elevated in the livers of HBV-infected human liver-chimeric mice. The knockdown or overexpression of GCN5 or the mutant of GCN5 could affect the binding of GCN5 to cccDNA or H3K79 succinylation, leading to a change in cccDNA transcription activity. In addition, Southern blot analysis validated that siGCN5 decreased the levels of cccDNA in the cells, suggesting that GCN5-mediated succinylation of histone H3K79 contributes to the epigenetic regulation of cccDNA minichromosome. Strikingly, IFN-α effectively depressed histone H3K79 succinylation in HBV cccDNA minichromosome in de novo HepG2-NTCP and HBV-infected HepaRG cells. Conclusions IFN-α epigenetically regulates the HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Our findings provide new insights into the mechanism by which IFN-α modulate the epigenetic regulation of HBV cccDNA minichromosome.

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Section: Introductionmentioning

confidence: 99%

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

Yuan

Yang

et al. 2020

Clin Epigenet

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“…In addition to histones, the succinylated proteins were found in the cytoplasm, nucleus, and mitochondria [7,21,22,23,24], indicating that lysine succinylation controls a variety of biological functions [14,18,25,26]. Lysine succinylation in HeLa cells induced different diseases via histone proteins, including UV-induced stress and cancer [12,27,28,29,30,31,32,33,34]. Therefore, identification of succinylation sites is a key to understanding the functional proteins.…”

Section: Introductionmentioning

confidence: 99%

Large-Scale Assessment of Bioinformatics Tools for Lysine Succinylation Sites

Hasan

Khatun

Kurata

2019

Cells

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Lysine succinylation is a form of posttranslational modification of the proteins that play an essential functional role in every aspect of cell metabolism in both prokaryotes and eukaryotes. Aside from experimental identification of succinylation sites, there has been an intense effort geared towards the development of sequence-based prediction through machine learning, due to its promising and essential properties of being highly accurate, robust and cost-effective. In spite of these advantages, there are several problems that are in need of attention in the design and development of succinylation site predictors. Notwithstanding of many studies on the employment of machine learning approaches, few articles have examined this bioinformatics field in a systematic manner. Thus, we review the advancements regarding the current state-of-the-art prediction models, datasets, and online resources and illustrate the challenges and limitations to present a useful guideline for developing powerful succinylation site prediction tools.

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“…hFEN1 undergoes multiple types of PTMs, including phosphorylation ( 21 ), methylation ( 22 ), acetylation ( 23 , 24 ), SUMOylation ( 25 ), ubiquitination ( 25 ) and succinylation ( 26 ). Of these PTMs, phosphorylation and methylation have been shown to antagonistically regulate hFEN1 activity ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Structural basis of 5′ flap recognition and protein–protein interactions of human flap endonuclease 1

Shi

Han

et al. 2018

Nucleic Acids Research

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Human flap endonuclease 1 (hFEN1) is a structure-specific nuclease essential for DNA replication and repair processes. hFEN1 has 5′ flap removal activity, as well as gap endonuclease activity that is critical for restarting stalled replication forks. Here, we report the crystal structures of wild-type and mutant hFEN1 proteins in complex with DNA substrates, followed by mutagenesis studies that provide mechanistic insight into the protein–protein interactions of hFEN1. We found that in an α-helix forming the helical gateway of hFEN1 recognizes the 5′ flap prior to its threading into the active site for cleavage. We also found that the β-pin region is rigidified into a short helix in R192F hFEN1–DNA structures, suppressing its gap endonuclease activity and cycle-dependent kinase interactions. Our findings suggest that a single mutation at the primary methylation site can alter the function of hFEN1 and provide insight into the role of the β-pin region in hFEN1 protein interactions that are essential for DNA replication and repair.

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Lysine Acetylation and Succinylation in HeLa Cells and their Essential Roles in Response to UV-induced Stress

Cited by 44 publications

References 29 publications

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

Large-Scale Assessment of Bioinformatics Tools for Lysine Succinylation Sites

Structural basis of 5′ flap recognition and protein–protein interactions of human flap endonuclease 1

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