Histone chaperone Asf1 is required for histone H3 lysine 56 acetylation, a modification associated with S phase in mitosis and meiosis

Recht, Judith; Tsubota, Toshiaki; Tanny, Jason C.; Diaz, R. L.; Berger, James M.; Zhang, X.; Garcia, Benjamin A.; Shabanowitz, Jeffrey; Burlingame, Alma L.; Hunt, Donald F.; Kaufman, Paul D.; Allis, C. David

doi:10.1073/pnas.0601676103

Cited by 235 publications

(292 citation statements)

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“…S. cerevisiae mutants lacking Rtt109 or Asf1 display delayed cell-cycle progression (15), spontaneous DNA damage (5,17,18), unstable replication forks, and are extremely sensitive to DNA-damaging agents (8). In accordance, point mutation of H3 lysine 56 to arginine, which cannot be acetylated and mimics a positively charged, unacetylated lysine, results in similar phenotypes (5,14). Therefore, acetylation of H3K56 is a particularly important PTM for fungal growth.…”

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confidence: 71%

“…In S. cerevisiae, H3K56 acetylation is required for replication fork stability (8,9), reassembly of chromatin after DNA damage repair, and histone association with chromatin assembly proteins (10)(11)(12)(13). A fungalspecific histone acetyl-transferase (HAT) enzyme, termed Rtt109, and its stimulatory histone chaperone cofactor, Asf1, are required for H3K56 acetylation (8,(14)(15)(16). S. cerevisiae mutants lacking Rtt109 or Asf1 display delayed cell-cycle progression (15), spontaneous DNA damage (5,17,18), unstable replication forks, and are extremely sensitive to DNA-damaging agents (8).…”

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confidence: 99%

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Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Rosa

Boyartchuk

Zhu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

127

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Candida albicans is a ubiquitous opportunistic pathogen that is the most prevalent cause of hospital-acquired fungal infections. In mammalian hosts, C. albicans is engulfed by phagocytes that attack the pathogen with DNA-damaging reactive oxygen species (ROS). Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity. To assess the importance of Rtt109 for C. albicans pathogenicity, we deleted the predicted homolog of Rtt109 in the clinical C. albicans isolate, SC5314. C. albicans rtt109 −/− mutant cells lack acetylated H3K56 (H3K56ac) and are hypersensitive to genotoxic agents. Additionally, rtt109 −/− mutant cells constitutively display increased H2A S129 phosphorylation and elevated DNA repair gene expression, consistent with endogenous DNA damage. Importantly, C. albicans rtt109 −/− cells are significantly less pathogenic in mice and more susceptible to killing by macrophages in vitro than are wild-type cells. Via pharmacological inhibition of the host NADPH oxidase enzyme, we show that the increased sensitivity of rtt109 −/− cells to macrophages depends on the host's ability to generate ROS, providing a mechanistic link between the drug sensitivity, gene expression, and pathogenesis phenotypes. We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds.acetylation | chromatin | fungal pathogenesis | DNA damage resistance | macrophage

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confidence: 71%

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confidence: 99%

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Rosa

Boyartchuk

Zhu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

127

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“…This modification is predicted to allow a looser interaction of the histones with DNA, suggesting that it may contribute to chromatin assembly (15,16). Interestingly, recent work has indicated that deletion of the gene encoding the histone chaperone Asf1 greatly reduces the levels of acetylation of H3 on lysine 56 (17,18). Similarly, our previous work had found that yeast lacking the histone chaperone Asf1 has greatly reduced levels of acetylation on lysine 9 of histone H3 (19).…”

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confidence: 97%

The Histone Chaperone Anti-silencing Function 1 Stimulates the Acetylation of Newly Synthesized Histone H3 in S-phase

Adkins

Carson

English

et al. 2007

Journal of Biological Chemistry

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Anti-silencing function 1 (Asf1) is a highly conserved chaperone of histones H3/H4 that assembles or disassembles chromatin during transcription, replication, and repair. We have found that budding yeast lacking Asf1 has greatly reduced levels of histone H3 acetylated at lysine 9. Lysine 9 is acetylated on newly synthesized budding yeast histone H3 prior to its assembly onto newly replicated DNA. Accordingly, we found that the vast majority of H3 Lys-9 acetylation peaked in S-phase, and this S-phase peak of H3 lysine 9 acetylation was absent in yeast lacking Asf1. By contrast, deletion of ASF1 has no effect on the S-phase specific peak of H4 lysine 12 acetylation; another modification carried by newly synthesized histones prior to chromatin assembly. We show that Gcn5 is the histone acetyltransferase responsible for the S-phase-specific peak of H3 lysine 9 acetylation. Strikingly, overexpression of Asf1 leads to greatly increased levels of H3 on acetylation on lysine 56 and Gcn5-dependent acetylation on lysine 9. Analysis of a panel of Asf1 mutations that modulate the ability of Asf1 to bind to histones H3/H4 demonstrates that the histone binding activity of Asf1 is required for the acetylation of Lys-9 and Lys-56 on newly synthesized H3. These results demonstrate that Asf1 does not affect the stability of the newly synthesized histones per se, but instead histone binding by Asf1 promotes the efficient acetylation of specific residues of newly synthesized histone H3.The eukaryotic genome is packaged into a nucleoprotein structure known as chromatin. The basic repeating unit of chromatin, the nucleosome, is made up of 147 base pairs of DNA wrapped around a histone octamer (two molecules each of histone proteins H2A, H2B, H3, and H4) (1). Chromatin provides a formidable obstacle to the cellular machinery gaining access to the DNA. Indeed, it is becoming apparent that chromatin is a highly dynamic structure that tightly regulates all nuclear processes that use DNA as a substrate; including transcription, DNA replication, repair, and recombination (2-4). Thus, the mechanisms by which chromatin structures are made and modified are fundamental questions of broad interest.The entire eukaryotic genome is assembled into chromatin following DNA replication, and this occurs in a stepwise manner; a tetramer of histones H3/H4 is deposited first followed by two dimers of H2A/H2B on the outside of the tetramer. Histone-binding proteins, termed histone chaperones, mediate chromatin assembly. It is known that when this process is coupled to DNA replication in vitro, it is mediated by the histone H3/H4 chaperone chromatin assembly factor 1 (CAF-1) 2 (5) together with another H3/H4 chaperone termed anti-silencing function 1 (Asf1) (6). CAF-1 and Asf1 have also been shown to localize to the sites of DNA replication (7, 8), supporting a role in assembling chromatin following DNA replication in vivo. The fact that CAF-1 and Asf1 co-purify with the replicationspecific histone variant H3.1 from HeLa cells is further evidence that Asf1 ...

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“…In human cells, it is proposed that Asf1 can disrupt parental nucleosomes (Groth et al, 2007). Furthermore, Asf1 is required for acetylation of histone H3 lysine 56 (H3K56Ac), a mark of newly-synthesized histones that has been found to be important for DNA replication and DNA repair (Recht et al, 2006;Chen et al, 2008;Li et al, 2008).…”

Section: The Function Of Three Histone Chaperones In Rc Nucleosome Asmentioning

confidence: 99%

Histones, histone chaperones and nucleosome assembly

Burgess

Zhang

2010

Protein Cell

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Chromatin structure governs a number of cellular processes including DNA replication, transcription, and DNA repair. During DNA replication, chromatin structure including the basic repeating unit of chromatin, the nucleosome, is temporarily disrupted, and then reformed immediately after the passage of the replication fork. This coordinated process of nucleosome assembly during DNA replication is termed replication-coupled nucleosome assembly. Disruption of this process can lead to genome instability, a hallmark of cancer cells. Therefore, addressing how replication-coupled nucleosome assembly is regulated has been of great interest. Here, we review the current status of this growing field of interest, highlighting recent advances in understanding the regulation of this important process by the dynamic interplay of histone chaperones and histone modifications.

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Histone chaperone Asf1 is required for histone H3 lysine 56 acetylation, a modification associated with S phase in mitosis and meiosis

Cited by 235 publications

References 32 publications

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

The Histone Chaperone Anti-silencing Function 1 Stimulates the Acetylation of Newly Synthesized Histone H3 in S-phase

Histones, histone chaperones and nucleosome assembly

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