Histone acetylation dynamics in repair of DNA double-strand breaks DOI Creative Commons
Shalini Aricthota,

Paresh Priyadarshan Rana,

Devyani Haldar

et al.

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 9, 2022

Packaging of eukaryotic genome into chromatin is a major obstacle to cells encountering DNA damage caused by external or internal agents. For maintaining genomic integrity, the double-strand breaks (DSB) must be efficiently repaired, as these are most deleterious type damage. The have detected in context, response (DDR) pathways activated repair either non‐ homologous end joining and recombination repair. It becoming clearer now that not mere hindrance DDR, it plays active role sensing, detection DSB governed reorganization pre-existing chromatin, leading recruitment specific machineries, remodelling complexes, histone modifiers bring about dynamic alterations composition, nucleosome positioning, modifications. In break, modulation occurs via various mechanisms including post-translational modification histones. induce many types modifications, such phosphorylation, acetylation, methylation ubiquitylation on residues which signal context dependent. break induced modifications been reported function sensing breaks, activating processing pathways, repairing damaged ensure integrity genome. Favourable environment for created generating open relaxed structure. Histone acetylation mediate de-condensation proteins their site action at facilitate this review, we will discuss current understanding critical inducing changes both organization promoting sites consists an overview regulation deacetylase enzymes remove marks regulators surveillance.

Language: Английский

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy DOI Creative Commons
Li Guo, Yuan Tian, Wei‐Guo Zhu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Sept. 29, 2020

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units chromatin. The fifth amino group (Nε) lysine residues is a common site for post-translational modifications (PTMs), these, acetylation second most common. Histone modulated by acetyltransferases (HATs) deacetylases (HDACs), involved in expression. Over past two decades, numerous studies characterizing HDACs HDAC inhibitors (HDACi) have provided novel exciting insights concerning their biological potential anti-cancer treatments. In this review, we detail diverse structures functions, including transcriptional regulation, metabolism, angiogenesis, damage response, cell cycle, apoptosis, protein degradation, immunity other several physiological processes. We also highlight avenues to use HDACi as novel, precision cancer

Language: Английский

Citations

271
SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis DOI Creative Commons
Mandy O. J. Grootaert, Alison Finigan,

Nichola Figg

et al.

Circulation Research, Journal Year: 2020, Volume and Issue: 128(4), P. 474 - 491

Published: Dec. 23, 2020

Rationale: Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved response signaling, inflammation, metabolism; however, its role regulating VSMC unclear. Objective: We examined expression human VSMCs, the role, regulation, downstream pathways activated by SIRT6, how regulates atherogenesis. Methods Results: protein, but not mRNA, was markedly reduced VSMCs mouse atherosclerotic plaques, derived from plaques or undergoing replicative palmitate-induced versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus HSC70-interacting protein) promoted stability, palmitate p38- c-Jun N-terminal kinase-dependent manner. bound to telomeres, while inhibition using shRNA deacetylase-inactive mutant (SIRT6 H133Y ) shortened lifespan induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation 53BP1 (p53 binding protein 1) binding, indicative damage. In contrast, overexpression preserved integrity, delayed cellular inflammatory cytokine changes metabolism senescence. , proliferation prevented senescence-associated metabolic changes. ApoE −/− (apolipoprotein E) mice were generated that overexpress only. SM22α-hSIRT6/ApoE had atherosclerosis, markers inflammation compared littermate controls, SM22α-hSIRT6 /ApoE showed increased instability. Conclusions: positively regulated CHIP. maintenance inhibits atherogenesis, all dependent on activity. Our data show endogenous an important unrecognized inhibitor atherosclerosis.

Language: Английский

Citations

182
Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation DOI Open Access
Miao Wang, Hening Lin

Annual Review of Biochemistry, Journal Year: 2021, Volume and Issue: 90(1), P. 245 - 285

Published: April 13, 2021

Protein lysine acetylation is an important posttranslational modification that regulates numerous biological processes. Targeting regulatory factors, such as acetyltransferases, deacetylases, and acetyl-lysine recognition domains, has been shown to have potential for treating human diseases, including cancer neurological diseases. Over the past decade, many other acyl-lysine modifications, succinylation, crotonylation, long-chain fatty acylation, also investigated interesting functions. Here, we provide overview of functions different modifications in mammals. We focus on it well characterized, principles learned from are useful understanding acylations. pay special attention sirtuins, given study sirtuins provided a great deal information about acylation. emphasize regulation illustrate their enables cells respond various signals stresses.

Language: Английский

Citations

117
Chromatin compartmentalization regulates the response to DNA damage DOI Creative Commons
Coline Arnould, Vincent Rocher,

Florian Saur

et al.

Nature, Journal Year: 2023, Volume and Issue: 623(7985), P. 183 - 192

Published: Oct. 18, 2023

Abstract The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in repair has been investigated 1,2 , chromosome folding these processes remains unclear 3 . Here we report that, after production double-stranded breaks (DSBs) mammalian cells, ATM drives formation a new compartment (D compartment) through clustering damaged topologically associating domains, decorated with γH2AX and 53BP1. This forms by mechanism that consistent polymer–polymer phase separation rather than liquid–liquid separation. D arises mostly G1 phase, independent cohesin enhanced pharmacological inhibition DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize compartment, this contributes their optimal activation, providing function for DSB response. However, DSB-induced reorganization comes at expense an increased rate translocations, also observed cancer genomes. Overall, characterize how compartmentalization orchestrates highlight critical impact architecture genomic instability.

Language: Английский

Citations

95
Chromatin accessibility: methods, mechanisms, and biological insights DOI Creative Commons
Andrés Mansisidor, Viviana I. Risca

Nucleus, Journal Year: 2022, Volume and Issue: 13(1), P. 238 - 278

Published: Nov. 20, 2022

Access to DNA is a prerequisite the execution of essential cellular processes that include transcription, replication, chromosomal segregation, and repair. How proteins regulate these function in context chromatin its dynamic architectures an intensive field study. Over past decade, genome-wide assays new imaging approaches have enabled greater understanding how access genome regulated by nucleosomes associated proteins. Additional mechanisms may control accessibility vivo compaction phase separation – are beginning be understood. Here, we review ongoing development measurements, summarize different molecular structural shape landscape, detail many important biological functions linked accessibility.

Language: Английский

Citations

74
SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases DOI Creative Commons
Zhenyang Guo, Peng Li, Junbo Ge

et al.

Aging and Disease, Journal Year: 2022, Volume and Issue: 13(6), P. 1787 - 1787

Published: Jan. 1, 2022

As an important NAD+-dependent enzyme, SIRT6 has received significant attention since its discovery. In view of observations that SIRT6-deficient animals exhibit genomic instability and metabolic disorders undergo early death, long been considered a protein longevity. Recently, growing evidence demonstrated functions as deacetylase, mono-ADP-ribosyltransferase fatty deacylase participates in variety cellular signaling pathways from DNA damage repair the stage to disease progression. this review, we elaborate on specific substrates molecular mechanisms various physiological pathological processes detail, emphasizing links aging (genomic damage, telomere integrity, repair), metabolism (glycolysis, gluconeogenesis, insulin secretion lipid synthesis, lipolysis, thermogenesis), inflammation cardiovascular diseases (atherosclerosis, cardiac hypertrophy, heart failure, ischemia-reperfusion injury). addition, most recent advances regarding modulators (agonists inhibitors) potential therapeutic agents for SIRT6-mediated are reviewed.

Language: Английский

Citations

72
SIRT1 and SIRT6: The role in aging-related diseases DOI Creative Commons
Yuzi You, Wei Liang

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(7), P. 166815 - 166815

Published: July 26, 2023

Aging is characterized by progressive functional deterioration with increased risk of mortality. It a complex biological process driven multitude intertwined mechanisms such as DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are family NAD+-dependent enzymes that regulate fundamental functions from genomic stability lifespan to energy metabolism tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 SIRT6 well-recognized for regulating signaling pathways related aging. Herein, we review protective role in aging-related diseases at molecular, cellular, tissue, whole-organism levels. We also discuss therapeutic potential modulators treatment these challenges thereof.

Language: Английский

Citations

54
SIRT6 is a key regulator of mitochondrial function in the brain DOI Creative Commons
Dmitrii Smirnov, Ekaterina Eremenko, Daniel Stein

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 18, 2023

Abstract The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it critical roles the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics metabolomics approaches characterize functions of mouse brains. Our analysis reveals that is a central regulator mitochondrial activity brain. deficiency leads with global downregulation mitochondria-related genes pronounced changes metabolite content. We suggest affects through interaction transcription factor YY1 that, together, regulate gene expression. Moreover, target include SIRT3 SIRT4, which are significantly downregulated SIRT6-deficient results demonstrate lack decreased expression metabolomic TCA cycle byproducts, including increased ROS production, reduced number, impaired membrane potential can be partially rescued by restoring SIRT4 levels. Importantly, observed brains also occurring aging human particularly patients Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic lateral sclerosis disease. Overall, our levels neurodegeneration initiate dysfunction altering expression, decay.

Language: Английский

Citations

49
Nuclear metabolism and the regulation of the epigenome DOI
Ruben Boon, Giórgia Gobbi da Silveira, Raúl Mostoslavsky

et al.

Nature Metabolism, Journal Year: 2020, Volume and Issue: 2(11), P. 1190 - 1203

Published: Oct. 12, 2020

Language: Английский

Citations

95
Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss DOI Creative Commons
Gayle B. Collin, Navdeep Gogna, Bo Chang

et al.

Cells, Journal Year: 2020, Volume and Issue: 9(4), P. 931 - 931

Published: April 10, 2020

Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions individuals worldwide, most frequently due photoreceptor (PR) cells. Animal models, particularly laboratory mouse, have been used understand pathogenic mechanisms that underlie PR cell and explore therapies may prevent, delay, reverse RD. Here, we reviewed entries Mouse Genome Informatics PubMed databases compile a comprehensive list monogenic mouse models which is demonstrated. The progression with postnatal age was documented mutant alleles genes grouped by biological function. As anticipated, wide range onset rate observed among reported models. analysis underscored relationships between RD ciliary function, transcription-coupled DNA damage repair, cellular chloride homeostasis. Comparing gene human identified RetNet database revealed are available for 40% known diseases, suggesting opportunities future research. This work provide insight into molecular players pathways through degenerative disease occurs be useful planning translational studies.

Language: Английский

Citations

77