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SIRT6 is of interest for its promising effect in the treatment of aging-related diseases. Studies have shown quercetin (QUE) and its derivatives have varying degrees of effect on the catalytic effect of SIRT6. In the research, the effect of QUE on the protein-substrate interaction in the SIRT6-mediated mono-ADP ribosylation system was investigated by conventional molecular dynamics (MD) simulations combined with MM/PBSA binding free energy calculations. The results show that QUE can bind stably to SIRT6 with the binding energy of -22.8 kcal/mol and further affect the atomic interaction between SIRT6 and NAD + (or H3K9), resulting in an increased affinity between SIRT6-NAD + and decreased SIRT6-H3K9 binding capacity. At the same time, the binding of QUE can also alter some structural characteristics of the protein, with large shifts occurring in the residue regions involving the N-terminal (residues 1-27), Rossmann fold regions (residues 55-92), and ZBD (residues 164-179). Thus, QUE shows great potential as a scaffold for the design of novel potent SIRT6 modulators., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Data obtained from cutting-edge research have shown that deregulated epigenetic marks are critical hallmarks of cancer. Rapidly emerging scientific evidence has helped in developing a proper understanding of the mechanisms leading to control of cellular functions, from changes in chromatin accessibility, transcription and translation, and in post-translational modifications. Firstly, mechanisms of DNA methylation and demethylation are introduced, as well as modifications of DNA and RNA, with particular focus on N6-methyladenosine (m6A), discussing the effects of these modifications in normal cells and in malignancies. Then, chromatin modifying proteins and remodelling complexes are discussed. Many enzymes and accessory proteins in these complexes have been found mutated or have undergone differential splicing, leading to defective protein complexes. Epigenetic mechanisms acting on nucleosomes by polycomb repressive complexes and on chromatin by SWI/SNF complexes on nucleosome assembly/disassembly, as well as main mutated genes linked to cancers, are reviewed. Among enzymes acting on histones and other proteins erasing the reversible modifications are histone deacetylases (HDACs). Sirtuins are of interest since most of these enzymes not only deacylate histones and other proteins, but also post-translationally modify proteins adding a Mono-ADP-ribose (MAR) moiety. MAR can be read by MACRO-domain containing proteins such as histone MacroH2A1, with specific function in chromatin assembly. Finally, recent advances are presented on non-coding RNAs with a scaffold function, prospecting their role in assembly of chromatin modifying complexes, recruiting enzyme players to chromatin regions. Lastly, the imbalance in metabolites production due to mitochondrial dysfunction is presented, with the potential of these metabolites to inhibit enzymes, either writers, readers or erasers of epitranscriptome marks. In the perspectives, studies are overwied on drugs under development aiming to limit excessive enzyme activities and to reactivate chromatin modifying complexes, for therapeutic application. This knowledge may lead to novel drugs and personalised medicine for cancer patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP) is an enzyme that adds a single ADP-ribose moiety to itself or other proteins. Tiparp is highly expressed in the brain; however, its function in this organ is unknown. Here, we used Tiparp -/- mice to determine Tiparp's role in the development of the prefrontal cortex. Loss of Tiparp resulted in an aberrant organization of the mouse cortex, where the upper layers presented increased cell density in the knock-out mice compared with wild type. Tiparp loss predominantly affected the correct distribution and number of GABAergic neurons. Furthermore, neural progenitor cell proliferation was significantly reduced. Neural stem cells (NSCs) derived from Tiparp -/- mice showed a slower rate of migration. Cytoskeletal components, such as α-tubulin are key regulators of neuronal differentiation and cortical development. α-tubulin mono-ADP ribosylation (MAR) levels were reduced in Tiparp -/- cells, suggesting that Tiparp plays a role in the MAR of α-tubulin. Despite the mild phenotype presented by Tiparp -/- mice, our findings reveal an important function for Tiparp and MAR in the correct development of the cortex. Unravelling Tiparp's role in the cortex, could pave the way to a better understanding of a wide spectrum of neurological diseases which are known to have increased expression of TIPARP ., (Copyright © 2019 Grimaldi et al.)