Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.

https://cshperspectives.cshlp.org/content/6/4/a018713.full.pdf?cited-by=yes;6/4/a018713

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

Lysine acetylation is a conserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellular signalling. Recent advances in the identification and quantification of lysine acetylation by mass spectrometry have increased our understanding of lysine acetylation, implicating it in many biological processes through the regulation of protein interactions, activity and localization. In addition, proteins are frequently modified by other types of acylations, such as formylation, butyrylation, propionylation, succinylation, malonylation, myristoylation, glutarylation and crotonylation. The intricate link between lysine acylation and cellular metabolism has been clarified by the occurrence of several such metabolite-sensitive acylations and their selective removal by sirtuin deacylases. These emerging findings point to new functions for different lysine acylations and deacylating enzymes and also highlight the mechanisms by which acetylation regulates various cellular processes.

The growing landscape of lysine acetylation links metabolism and cell signalling

Sirtuin 6 (SIRT6) is a mammalian homolog of the yeast Sir2 deacetylase. Mice deficient for SIRT6 exhibit genome instability. Here, we show that in mammalian cells subjected to oxidative stress SIRT6 is recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination. Our results indicate that SIRT6 physically associates with poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly-ADP-ribosylase activity and enhancing DSB repair under oxidative stress.

/pdf/sirt6-promotes-dna-repair-under-stress-by-activating-parp1-3wlhrnl7su.pdf

SIRT6 promotes DNA repair under stress by activating PARP1.

Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggests that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this Review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, the acylation 'reader' proteins that mediate the effects of different acylations and their physiological functions, which include signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.

Metabolic regulation of gene expression through histone acylations

DNA double-strand break (DSB) repair occurs within chromatin and can be modulated by chromatin-modifying enzymes. Here we identify the related human histone deacetylases HDAC1 and HDAC2 as two participants in the DNA-damage response. We show that acetylation of histone H3 Lys56 (H3K56) was regulated by HDAC1 and HDAC2 and that HDAC1 and HDAC2 were rapidly recruited to DNA-damage sites to promote hypoacetylation of H3K56. Furthermore, HDAC1- and 2-depleted cells were hypersensitive to DNA-damaging agents and showed sustained DNA-damage signaling, phenotypes that reflect defective DSB repair, particularly by nonhomologous end-joining (NHEJ). Collectively, these results show that HDAC1 and HDAC2 function in the DNA-damage response by promoting DSB repair and thus provide important insights into the radio-sensitizing effects of HDAC inhibitors that are being developed as cancer therapies.

Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining.

Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD(+)-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo.

/pdf/sirt7-links-h3k18-deacetylation-to-maintenance-of-oncogenic-2l93r03c2r.pdf

SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

SIRT6 is a member of the Sir2 (Silent Information Regulator-2) family of genes, which regulate fundamental processes in aging and lifespan control in multiple organisms.1-3 SIRT6 deficiency in mice results in genomic instability, metabolic defects, and degenerative phenotypes associated with aging.1 Previously, we showed that SIRT6 deacetylates lysine 9 on the N-terminal tail of histone H3 (H3K9Ac) to modulate telomeric chromatin and gene expression.2,3 Here, we identify a second substrate of SIRT6 at chromatin, lysine 56 on the globular core of histone H3 (H3K56Ac). We show that SIRT6 deacetylates H3K56Ac in vitro and in cells, and identify a physiologic role for this activity in maintaining dynamic changes of H3K56 acetylation levels at telomeric chromatin over the cell cycle. Together, these findings provide the first analysis of how H3K56Ac levels are dynamically regulated at human telomeres in response to a mammalian SIRT.

Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6

Interferon-Inducible GTPases in Host Resistance, Inflammation and Disease.

Iron sequestration provides an innate defense, termed nutritional immunity, leading pathogens to scavenge iron from hosts. Although the molecular basis of this battle for iron is established, its potential as a force for evolution at host-pathogen interfaces is unknown. We show that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens.

/pdf/escape-from-bacterial-iron-piracy-through-rapid-evolution-of-3ypg3u1bbf.pdf

Escape from bacterial iron piracy through rapid evolution of transferrin.

https://www.cell.com/trends/genetics/pdf/S0168-9525(15)00161-4.pdf

Matthew F. Barber

Papers

SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6

Interferon-Inducible GTPases in Host Resistance, Inflammation and Disease.

Escape from bacterial iron piracy through rapid evolution of transferrin.

Buried Treasure: Evolutionary Perspectives on Microbial Iron Piracy.