Genetic Analysis of Histone H4: Essential Role of Lysines Subject to Reversible Acetylation

Megee, Paul C.; Morgan, Brian A.; Mittman, Barbara A.; Smith, M. Mitchell

doi:10.1126/science.2106160

Cited by 327 publications

(291 citation statements)

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“…Deletion mutants in the C‐terminus (Δ648–757 and Δ655–662) significantly blunted SIRT1‐dependent autophagy induction, while N‐terminal mutations (Δ2–92 and Δ262–392) did not (Figure 6b), indicating integral roles of the C‐terminus of MFN2 in SIRT1‐mediated induction of autophagy. To specify C‐terminal Lys residues that are functionally tied to autophagy enhancement, point mutants were generated to mimic Lys deacetylation by substituting Lys with arginine (Arg), which conserves the net positive charge of Lys but prevents charge neutralization by acetylation (Megee, Morgan, Mittman & Smith, 1990). As the C‐terminal sequence between 648 and 757 is likely involved in SIRT1‐dependent autophagy, we reasoned that K‐to‐R substitution in the C‐terminus would enhance autophagy even without SIRT1 overexpression.…”

Section: Resultsmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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SummaryIschemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age‐mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near‐complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co‐overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C‐terminus of MFN2, leading to autophagy activation. The SIRT1‐MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

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Section: Resultsmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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“…However, the K16 mutation to arginine is apparently the only single mutation that shows a clear significant increase in Sphase length (around 10 min longer) and a decrease in G 2 /M (around 7 min) (Megee et al, 1990(Megee et al, , 1995.…”

Section: Histone H4 Lysine 16 Acetylationmentioning

confidence: 97%

“…tail is dispensable for viability in yeast (Kayne et al, 1988), its loss is associated with defects in transcription (Durrin et al, 1991), cell-cycle progression (Megee et al, 1990), DNA repair (Bird et al, 2002), silencing (Johnson et al, 1990), and mating efficiency (Kayne et al, 1988;Park and Szostak, 1990). This requirement for the H4 tail lies in its four acetylatable lysines, as single substitution mutations of these lysines to either glutamine or arginine (which mimic acetylated or deacetylated lysine, respectively) show quite different outputs (Park and Szostak, 1990).…”

Section: Histone H4 Lysine 16 Acetylationmentioning

confidence: 99%

“…In fact, H4K16Ac seems to be involved in DNA replication in plants (Belyaev et al, 1997), similar to H4K5Ac and H4K12Ac. Interestingly, substitution of H4K16 to arginine (to mimic nonacetylated lysine) resulted in a lengthening of S phase in yeast (Megee et al, 1990). It is important to note that the effects mediated by SirT2 loss might also be due to its putative role in cytoskeleton regulation or another yet to be identified role (Figure 4a).…”

Section: Sirt2mentioning

confidence: 99%

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NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

2007

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Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I-IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes.

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“…The essential role of the acetylation of histone H4 lysines and its importance in maintaining the genome integrity came from three studies in the early 1990s. These studies showed that cells bearing several different mutations in the N termini of histone H4 exhibit cell cycle arrest at G 2 /M phase and compromised genomic stability (Megee et al, 1990(Megee et al, , 1995Durrin et al, 1991;Morgan et al, 1991). However, one of the first evidences of the involvement of histone acetylation in DNA repair was provided by Nakatani and collaborators who showed that Tip60 HAT was involved in DNA repair and that mutations in the acetylase activity of Tip60 resulted in cells with deficient DNA repair (Ikura et al, 2000).…”

Section: Dna Repairmentioning

confidence: 99%

Orchestration of chromatin-based processes: mind the TRRAP

et al. 2007

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Chromatin modifications at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modification; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases (HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein (TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer.

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Genetic Analysis of Histone H4: Essential Role of Lysines Subject to Reversible Acetylation

Cited by 327 publications

References 33 publications

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

Orchestration of chromatin-based processes: mind the TRRAP

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