H3K56

Structurally diverse acylations have been identified as post-translational modifications (PTMs) on histone lysine residues, but their functions and regulations remain largely unknown. Interestingly, in nature, a lysine acylation analog, pyrrolysine, is introduced as a co-translational modification (CTM) through genetic encoding. To explore this alternative life form, we created a model organism Saccharomyces cerevisiae containing site-specific lysine CTMs (acetyl-lysine, crotonyl-lysine, or another synthetic analog) at histone H3K56 using non-canonical amino acid mutagenesis to afford a chemically modified nucleosome in lieu of their own in vivo...

DNA replication perturbs chromatin by triggering the eviction, replacement and incorporation of nucleosomes. How this dynamic is orchestrated in time and space is poorly understood. Here, we apply a genomically encoded sensor for histone exchange to follow the time-resolved histone H3 exchange profile in budding yeast cells undergoing slow synchronous replication in nucleotide limiting conditions. We find that new histones are incorporated not only behind, but also ahead of the replication fork. We provide evidence that Rtt109, the S phase-induced acetyltransferase, stabilizes nucleosomes behind the fork, but promotes H3 replacement ahead of the fork...

H3K56 acetylation (H3K56Ac) was reported to play a critical role in chromatin assembly; thus, H3K56ac participates in the regulation of DNA replication, cell cycle progression, DNA repair, and transcriptional activation. To investigate the influence of DNA damage regulators on the acetylation of histone H3 and gene transcription, U2OS cells expressing SNAP-labeled H3.1 or SNAP-labeled H3.3 were treated with ATM, ATR, or a Chk1 inhibitor after ultraviolet (UV) radiation. The levels of H3.1K56ac, H3.3K56ac, and other H3 site-specific acetylation were checked at different time points until 24 h after UV radiation...

Crucial mechanisms are required to restrict self-propagating heterochromatin spreading within defined boundaries and prevent euchromatic gene silencing. In the filamentous fungus Neurospora crassa, the JmjC domain protein DNA METHYLATION MODULATOR-1 (DMM-1) prevents aberrant spreading of heterochromatin, but the molecular details remain unknown. Here, we revealed that DMM-1 is highly enriched in a well-defined 5-kb heterochromatin domain upstream of the cat-3 gene, hereby called 5H-cat-3 domain, to constrain aberrant heterochromatin spreading...

Gram-negative intracellular pathogen Vibrio parahaemolyticus manifests its infection through a series of effector proteins released into the host via the type III secretion system. Most of these effector proteins alter signalling pathways of the host to facilitate survival and proliferation of bacteria inside host cells. Here, we report V. parahaemolyticus (serotype O3:K6) infection-induced histone deacetylation in host intestinal epithelial cells, particularly deacetylation of H3K9, H3K56, H3K18 and H4K16 residues...

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance...

BACKGROUND: Asf1 is a well-conserved histone chaperone that regulates multiple cellular processes in different species. Two paralogous genes, Asf1a and Asf1b exist in mammals, but their role during fertilization and early embryogenesis remains to be investigated further. METHODS: We analyzed the dynamics of histone chaperone Asf1a and Asf1b in oocytes and pre-implantation embryos in mice by immunofluorescence and real-time quantitative PCR, and further investigated the role of Asf1a and Asf1b during fertilization and pre-implantation development by specific Morpholino oligos-mediated knock down approach...

This study focuses on sirtuins, which catalyze the reaction of NAD+ -dependent protein deacetylase, for riboflavin production in A. gossypii. Nicotinamide, a known inhibitor of sirtuin, made the color of A. gossypii colonies appear a deeper yellow at 5 mM. A. gossypii has 4 sirtuin genes (AgHST1, AgHST2, AgHST3, AgHST4) and these were disrupted to investigate the role of sirtuins in riboflavin production in A. gossypii. AgHST1∆, AgHST3∆, and AgHST4∆ strains were obtained, but AgHST2∆ was not. The AgHST1∆ and AgHST3∆ strains produced approximately 4...

The first order of DNA packaging is the nucleosome with the DNA wrapped around the histone octamer. This leaves the nucleosomal DNA with access restrictions, which impose a significant barrier to repair of damaged DNA. The efficiency of DNA repair has been related to nucleosome structure and chromatin status, which is modulated in part by post-translational modifications (PTMs) of histones. Numerous studies have suggested a role for acetylation of lysine at position 56 of the H3 histone (H3K56ac) in various DNA transactions, including the response to DNA damage and its association with human cancer...

The recent discovery of activator compounds binding to an allosteric site on the NAD+ -dependent protein lysine deacetylase, sirtuin 6 (SIRT6) has attracted interest and presents a pharmaceutical target for aging-related and cancer diseases. However, the mechanism underlying allosteric activation of SIRT6 by the activator MDL-801 remains largely elusive because no major conformational changes are observed upon activator binding. By combining molecular dynamics simulations with biochemical and kinetic analyses of wild-type SIRT6 and its variant M136A, we show that conformational rotation of 2-methyl-4-fluoro-5-bromo substituent on the right phenyl ring (R-ring) of MDL-801, which uncovers previously unseen hydrophobic interactions, contributes to increased activating deacetylation activity of SIRT6...

H3K56 acetylation (H3K56Ac) was first identified in yeast and has recently been reported to play important roles in maintaining genomic stability, chromatin assembly, DNA replication, cell cycle progression and DNA repair. Although H3.1K56Ac has been relatively well studied, the function of H3.3K56Ac remains mostly unknown in mammals. In this study, we used H3.3K56Q and H3.3K56R mutants to study the possible function of H3.3K56 acetylation. The K-to-Q substitution mimics a constitutively acetylated lysine, while the K-to-R replacement mimics a constitutively unmodified lysine...

INTRODUCTION: Valproic acid (VPA), a widely prescribed antiepileptic drug and an effective treatment for bipolar disorder and neuropathic pain, results in multiple developmental defects following in utero exposure. Uterine decidua provides nutritional and physical support during implantation and early embryonic development. Perturbations in the molecular mechanisms within decidual tissue during early pregnancy might affect early embryonic growth, result in early pregnancy loss or cause complications in the later gestational stage...

Tandem repeats are inherently unstable and exhibit extensive copy number polymorphisms. Despite mounting evidence for their adaptive potential, the mechanisms associated with regulation of the stability and copy number of tandem repeats remain largely unclear. To study copy number variation at tandem repeats, we used two well-studied repetitive arrays in the budding yeast genome, the ribosomal DNA (rDNA) locus, and the copper-inducible CUP1 gene array. We developed powerful, highly sensitive, and quantitative assays to measure repeat instability and copy number and used them in multiple high-throughput genetic screens to define pathways involved in regulating copy number variation...

As cells replicate their DNA, there is a need to synthesize new histones with which to wrap it. Newly synthesized H3 histones that are incorporated into the assembling chromatin behind the replication fork are acetylated at lysine 56. The acetylation is removed by two deacetylases, Hst3 and Hst4. This process is tightly regulated and any perturbation leads to genomic instability and replicative stress. We recently showed that Dun1, a kinase implicated mainly in the regulation of dNTPs, is vital in cells with hyper-acetylation, to counteract Rad53's inhibition on late-firing origins of replication...

Saccharomyces cerevisiae exhibits gene expression homeostasis, which is defined as the buffering of transcription levels against changes in DNA copy number during the S phase of the cell cycle. It has been suggested that S. cerevisiae employs an active mechanism to maintain gene expression homeostasis through Rtt109-Asf1-dependent acetylation of histone H3 on lysine 56 (H3K56). Here, we show that gene expression homeostasis can be achieved independently of H3K56 acetylation by Tos4 (Target of Swi6-4). Using Nanostring technology we establish that Tos4-dependent gene expression homeostasis depends on its forkhead-associated (FHA) domain, which is a phosphopeptide recognition domain required to bind histone deacetylases (HDACs)...

Acetylation on lysine 56 of histone H3 of the yeast Saccharomyces cerevisiae has been implicated in many cellular processes that affect genome stability. Despite being the object of much research, the complete scope of the roles played by K56 acetylation is not fully understood even today. The acetylation is put in place at the S-phase of the cell cycle, in order to flag newly synthesized histones that are incorporated during DNA replication. The signal is removed by two redundant deacetylases, Hst3 and Hst4, at the entry to G2/M phase...

During DNA replication newly synthesized histones are incorporated into the chromatin of the replicating sister chromatids. In the yeast Saccharomyces cerevisiae new histone H3 molecules are acetylated at lysine 56. This modification is carefully regulated during the cell cycle, and any disruption of this process is a source of genomic instability. Here we show that the protein kinase Dun1 is necessary in order to maintain viability in the absence of the histone deacetylases Hst3 and Hst4, which remove the acetyl moiety from histone H3...

In eukaryotic cells, changes in chromatin accessibility are necessary for chromatin to maintain its highly dynamic nature at different times during the cell cycle. Histone chaperones interact with histones and regulate chromatin dynamics. Facilitates chromatin transcription (FACT) is an important histone chaperone that plays crucial roles during various cellular processes. Here, we analyze the structural characteristics of FACT, discuss how FACT regulates nucleosome/chromatin reorganization and summarize possible functions of FACT in transcription, replication, and DNA repair...

Nasopharyngeal carcinoma (NPC) is a head and neck cancer with severe local invasion and early distant metastasis. SIRT6 serves as a critical modulator of the development and metastasis of multiple types of cancer; however, the roles and underlying mechanisms of SIRT6 in regulating NPC metastasis remain largely unknown. Here, the expression of SIRT6 in high metastatic 5-8F cells and low metastatic 6-10B cells was analyzed. SIRT6 expression was found to be negatively associated with the metastatic capability of NPC cells...

As a member of Sirtuins family, SIRT6 participates in the physiological and pathological progress of DNA repair, anti-aging, metabolism, and so on. Several studies have demonstrated that knockdown of SIRT6 inhibited the development of atherosclerosis (AS), indicated SIRT6 as a protective factor for AS. However, we confirmed SIRT6 was significantly overexpressed in human unstable carotid plaques compared with stable carotid plaques. This result indicated a more complex role of SIRT6 in AS. Furthermore, we constructed mice model with unstable carotid plaque and injected them with SIRT6 overexpressed adeno-associated virus (AAV-SIRT6)...