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Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Acetylation at lysine residues represents an abundant highlighted mark known to display its role in the regulatory mechanism of cellular processes like transcription. Acetylation at the histone residues of H/H4 is directly correlated with the expression of the gene. Bromodomain, structural motifs, act as epigenetic readers present in all different proteins that play a specific role in recognizing acetylated lysines and transcriptional regulation [41]. Despite direct effector recruitment, histone acetylation introduces certain changes in the structure of chromatin physically by neutralizing observable charge of lysines residues and disrupts the intra- and inter-nucleosomal interactions results in the open structure of chromatin, which provide the permissible environment for transcription. Acetylation of these three lysine residues on H3-based globular domains, H3K122, H3K64, and H3K56, is present on the H3–DNA interface that might disrupt nucleosomal interactions and also is directly linked with gene activation [43–45]. H3K122ac, lysine residue, has also shown its role to promote in vitro transcription by means of process stimulation of histone eviction [44]. Acetylation at the tail of H3 and H4 histone residues stimulates DNA unwrapping, whereas acetylation at H3 residues plays a role in nucleosome sensitization towards salt-induced dissociation [46]. H3/H4 and H3K4me3 acetylation generally coexist at TSS and promoter regions of specific active genes.
The Genetic Program of Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Xiufang Wang, Huanling Zhang, Libo Su, Zhanjun Lv
Histone acetylation directly affects the physical association of histones and DNA. Evidence suggests that the pattern of histone acetylation changes during normal aging. The global levels of H3K56ac decrease during replicative aging in yeast, while those of H4K16ac increase, resulting in de-silencing of telomeric repeats (Dang et al., 2009). Global H4K16ac levels reduce during normal aging and in a mouse model of Hutchinson–Gilford progeria syndrome (HGPS) and may be linked, at least in the progeroid model, to a decreased association of histone acetyltransferases (HAT) with the nuclear periphery (Krishnan et al., 2011). Following contextual fear conditioning, older mice cannot upregulate H4K12ac, a mark that accelerates transcriptional elongation (Hargreaves et al., 2009), in their hippocampus, and this relates to changed gene expression and memory impairment (Peleg et al., 2010). Alterations in histone acetylation may be a result and a cause of the failure of older cells to transduce external stimuli to downstream transcriptional responses, a process that is detrimental for rapid cell-to-cell signaling in the brain. Both HAT and deacetylases (HDAC) regulate life span and metabolic health. For example, H4K16ac is deacetylated by the sirtuin SIR263, and reduced SIR2 dosage prolongs life span in S. cerevisiae (Kaeberlein et al., 1999) by limiting aberrant recombination at the ribosomal DNA locus. More generally, sirtuins may have a pro-longevity role by promoting enhanced genomic stability (Mostoslavsky et al., 2006; Toiber et al., 2013; Van Meter et al., 2014).
Sirtuin modulators: where are we now? A review of patents from 2015 to 2019
Published in Expert Opinion on Therapeutic Patents, 2020
Nicola Mautone, Clemens Zwergel, Antonello Mai, Dante Rotili
SIRT6 is a NAD+-dependent mono ADP-ribosyltransferase and, mainly, a protein lysine deacylase (deacetylase and defatty-acylase), that has recently emerged as a key epigenetic regulator of chromatin dynamics, genome stability, and nuclear signaling programs crucial for human health and disease prevention [2,52,53]. The capability to selectively catalyze the deacetylation of various histone substrates depending on cellular or genomic contexts (H3K9, H3K18, and H3K56) has been linked to the modulation of many processes that are dysregulated in metabolic syndromes, aging, and cancer, including DNA damage responses, heterochromatin silencing, lipid and glucose homeostasis, stem cell functions, and circadian regulation [53]. SIRT6 is also linked to tissue-specific inflammation, regulating the secretion of TNF-α via its demyristoylase activity [53]. In cancer, SIRT6-dependent deacetylation seems to promote tumor suppressor effects, with reduced levels of the enzyme that can contribute to cancer progression in various types of malignancies [53]. However, in specific tumor contexts, high levels of SIRT6 may affect cancer progression in a complex way [53].
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
Most specific histone acetylation sites do not change appreciably after damage but a study from Jackson lab reported that H3 acetylated at Lys9 (H3K9Ac) and H3Lys56Ac (H3K56Ac) are rapidly deacetylated in response to DNA damage in human cells (Tjeertes et al. 2009). Pre-existing modifications also influence the DNA damage response at the level of signaling. For example, depletion of MOF in human cells leads to reduction in H4Lys16Ac (H4K16Ac) levels and such cells have reduced levels of ATM activation (Gupta et al. 2005) as well as defective appearance of γH2AX foci after irradiation. Furthermore, Sharma et al. demonstrated a relationship between H4K16Ac levels and DNA damage response in differentiated HL60 cells where reduced H4K16Ac levels resulted in a decrease in the frequency of γH2AX foci per cell after irradiation (Gupta et al. 2005; Sharma GG et al. 2010).
Recent advances in histone modification and histone modifying enzyme assays
Published in Expert Review of Molecular Diagnostics, 2019
Fei Ma, Su Jiang, Chun-yang Zhang
Histones are highly basic proteins present in all eukaryotic cells and they are important components of chromatin [1]. Generally, two copies of each of the core histones H2A, H2B, H3, and H4 make up the histone octamer which is wrapped by 147 bp of DNA to form nucleosome core particle; the core particle is linked by the linker DNA to form a complete nucleosome, and the repeating nucleosomes are further condensed into a higher order chromatin when linker histone H1 binds to the linker DNA [2,3]. Although histones were found for the first time in 1884 [4], their important biological effects have not come to researcher’s attention until the findings of some amino acids modifications existed in histone peptides [5]. From then on, many different histone modifications catalyzed by the corresponding histone-modifying enzymes have been discovered, such as methylation, acetylation, phosphorylation, ubiquitynation, sumoylation, biotinylation, and ADP-ribosylation [6,7]. These histone modifications play critical roles in many important cellular functions including gene expression regulation, heterochromatin formation, gene imprinting, DNA damage repair, and X chromosome inactivation [8–10]. For example, acetylation of lysine at position 56 of H3 (H3K56ac) is involved in the DNA damage repair [11]; tri-methylation of lysine 4 on histone H3 (H3K4me3) is associated with the transcription activation; tri-methylation of H3K9 (H3K9me3) and H3K27 (H3K27me3) are linked with the repressed chromatin regions [12]; the acetylation of H4 may alter the chromatin accumulation and recruit the repair proteins at sites of DNA damage [13]. Besides the above classical modifications, a series of new types of histone modifications are revealed recently, such as propionylation (Kpr), butyrylation (Kbu), and crotonylation (Kcr), which may be responsible for increasing the coding potential of other histone modifications [14–17].