Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study

The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new insights into the deprotonation process and the role of the catalytic machinery in the methyl-transfer reaction. Our finding suggests that the source of the activation mechanism comes from conformational restriction mediated by the formation of a network of salt-bridges between MLL3 and one of the activating subunits, which restricts and stabilizes the positioning of several residues relevant for the catalysis. New insights into the deprotonation mechanism of lysine are provided, identifying a valine residue as crucial in the positioning of the water molecule in charge of the process. Finally, a tyrosine residue was found to assist the methyl transfer from SAM to the target lysine.

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The Functions of the Demethylase JMJD3 in Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22020968 ◽

2021 ◽

Vol 22 (2) ◽

pp. 968

Author(s):

Anna Sanchez ◽

Fatma Zohra Houfaf Khoufaf ◽

Mouhamed Idrissou ◽

Frédérique Penault-Llorca ◽

Yves-Jean Bignon ◽

...

Keyword(s):

Epigenetic Mark ◽

Cancer Type ◽

Epigenetic Changes ◽

Scientific Review ◽

H3k27 Methylation ◽

Histone 3 ◽

Wide Range ◽

Development Data ◽

Sports Activities

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3’s involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.

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STRUCTURAL COMPONENTS OF THE PRIVATE MEDICAL SECTOR ACTIVATION MECHANISM

Economical ◽

10.31474/1680-0044-2019-2(21)-170-177 ◽

2019 ◽

Vol 2 (2(21)) ◽

pp. 170-177

Author(s):

Anzhela Bairak ◽

Keyword(s):

Health Care ◽

Health Care System ◽

Activation Mechanism ◽

Practical Significance ◽

Structural Components ◽

Medical Sector ◽

Analysis And Synthesis ◽

Private Medicine ◽

Care System

The article examines the problems of private medicine in the health care system of the country. The aim of the article is to determine the structural components of the mechanism of activation of the private medical sector as a reserve for the provision of quality and affordable medical services and a driver for the development of the medical industry. The descriptive-analytical method, methods of analysis and synthesis, comparison, statistical, analysis and scientific generalization were used in the paper. The study substantiates the strengthening of the role of the private medical sector in the health care management system. The key problems of the domestic private medical sector and the restraining factors of its development are identified. It is concluded that it is necessary to develop a mechanism to promote the development of private medicine through a policy of active change in the health care system. The directions of activation of the private medical sector as a target reference point in the process of determining the structural elements of the organizational and economic mechanism are outlined. The structural detail of the mechanism of activation of the private medical sector for optimization of the health care system is offered. The practical significance of the obtained results is that the results of the research presented in the article are a practical basis for the development and improvement of mechanisms of public administration in the field of health care.

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Faculty Opinions recommendation of Structural and kinetic evidence for an extended hydrogen-bonding network in catalysis of methyl group transfer. Role of an active site asparagine residue in activation of methyl transfer by methyltransferases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1067744.520660 ◽

2007 ◽

Author(s):

Rowena Matthews

Keyword(s):

Hydrogen Bonding ◽

Active Site ◽

Methyl Group ◽

Group Transfer ◽

Methyl Transfer ◽

Hydrogen Bonding Network ◽

Asparagine Residue ◽

Methyl Group Transfer

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Epigenetic Regulator Signatures in Regenerative Capacity

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190618125111 ◽

2019 ◽

Vol 14 (7) ◽

pp. 598-606

Author(s):

Sarah Albogami

Keyword(s):

Epigenetic Regulation ◽

Animal Species ◽

Current Knowledge ◽

Regeneration Process ◽

Body Parts ◽

Lysine Methylation ◽

Regenerative Capacity ◽

Biological Phenomena ◽

Epigenetic Regulator

Background:: Regeneration is the process by which body parts lost as a result of injury are replaced, as observed in certain animal species. The root of regenerative differences between organisms is still not very well understood; if regeneration merely recycles developmental pathways in the adult form, why can some animals regrow organs whereas others cannot? In the regulation of the regeneration process as well as other biological phenomena, epigenetics plays an essential role. Objective:: This review aims to demonstrate the role of epigenetic regulators in determining regenerative capacity. Results:: In this review, we discuss the basis of regenerative differences between organisms. In addition, we present the current knowledge on the role of epigenetic regulation in regeneration, including DNA methylation, histone modification, lysine methylation, lysine methyltransferases, and the SET1 family. Conclusion:: An improved understanding of the regeneration process and the epigenetic regulation thereof through the study of regeneration in highly regenerative species will help in the field of regenerative medicine in future.

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The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation

Nature Communications ◽

10.1038/s41467-021-23809-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xiaoping Xu ◽

Kai Ni ◽

Yafeng He ◽

Jianke Ren ◽

Chongkui Sun ◽

...

Keyword(s):

Chromatin Remodeling ◽

Critical Role ◽

Genomic Stability ◽

Dna Degradation ◽

Replication Forks ◽

Filament Formation ◽

Epigenetic Regulator ◽

Centromeric Instability ◽

Stalled Replication Forks

AbstractThe Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks and the generation of genomic instability. The protection of stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. LSH or macroH2A deficiency leads to an impairment of RAD51 loading, a factor that prevents MRE11 and EXO1 mediated nascent DNA degradation. The defect in RAD51 loading is linked to a disbalance of BRCA1 and 53BP1 accumulation at stalled forks. This is associated with perturbed histone modifications, including abnormal H4K20 methylation that is critical for BRCA1 enrichment and 53BP1 exclusion. Altogether, our results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated chromatin remodeling in genomic stability.

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PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

International Journal of Molecular Sciences ◽

10.3390/ijms22105112 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5112

Author(s):

Lotte van Beek ◽

Éilís McClay ◽

Saleha Patel ◽

Marianne Schimpl ◽

Laura Spagnolo ◽

...

Keyword(s):

Dna Damage ◽

Dna Binding ◽

Parp Inhibitors ◽

Covalent Modification ◽

Activation Mechanism ◽

Cancer Therapies ◽

Damage Repair ◽

Complementary Role ◽

Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

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The Leucine Catabolite and Dietary Supplement β-Hydroxy-β-Methyl Butyrate (HMB) as an Epigenetic Regulator in Muscle Progenitor Cells

Metabolites ◽

10.3390/metabo11080512 ◽

2021 ◽

Vol 11 (8) ◽

pp. 512

Author(s):

Virve Cavallucci ◽

Giovambattista Pani

Keyword(s):

Histone Acetylation ◽

Dietary Supplement ◽

Hdac Inhibitor ◽

Muscle Wasting ◽

C2c12 Cells ◽

Myoblast Differentiation ◽

Epigenetic Mark ◽

Epigenetic Regulator ◽

Methyl Butyrate

β-Hydroxy-β-Methyl Butyrate (HMB) is a natural catabolite of leucine deemed to play a role in amino acid signaling and the maintenance of lean muscle mass. Accordingly, HMB is used as a dietary supplement by sportsmen and has shown some clinical effectiveness in preventing muscle wasting in cancer and chronic lung disease, as well as in age-dependent sarcopenia. However, the molecular cascades underlying these beneficial effects are largely unknown. HMB bears a significant structural similarity with Butyrate and β-Hydroxybutyrate (βHB), two compounds recognized for important epigenetic and histone-marking activities in multiple cell types including muscle cells. We asked whether similar chromatin-modifying actions could be assigned to HMB as well. Exposure of murine C2C12 myoblasts to millimolar concentrations of HMB led to an increase in global histone acetylation, as monitored by anti-acetylated lysine immunoblotting, while preventing myotube differentiation. In these effects, HMB resembled, although with less potency, the histone deacetylase (HDAC) inhibitor Sodium Butyrate. However, initial studies did not confirm a direct inhibitory effect of HMB on HDACs in vitro. β-Hydroxybutyrate, a ketone body produced by the liver during starvation or intense exercise, has a modest effect on histone acetylation of C2C12 cells or in vitro HDAC inhibitor activities, and, unlike Butyrate and HMB, did not interfere with myotube formation in a myoblast differentiation assay. Instead, βHB dramatically increased lysine β-hydroxybutyrylation (Kbhb) of histone tails, an epigenetic mark associated with fasting responses and muscle catabolic states. However, when C2C12 cells were exposed to βHB in the presence of equimolar HMB this chromatin modification was drastically reduced, pointing to a role for HMB in attenuating ketosis-associated muscle wasting. In conclusion, while their mechanistic underpinnings remain to be clarified, these preliminary observations highlight novel and potentially important activities of HMB as an epigenetic regulator and βHB antagonist in muscle precursor cells, to be further explored in their biomedical implications.

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