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1. Pf GCN5 is essential for Plasmodium falciparum survival and transmission and regulates Pf H2B.Z acetylation and chromatin structure

   https://doi.org/10.1093/nar/gkaf218  

   Tang, Jingyi; Yeoh, Lee M.; Grotz, Myriam D.; Goodman, Christopher D.; Chisholm, Scott A.; Nguyen, Hanh H_T; Yu, Chunhao; Pareek, Kapil; McPherson, Fairley; Cozijnsen, Anton; et al (March 2025, Nucleic Acids Research)

   Abstract Plasmodium falciparum causes most malaria deaths. Its developmental transitions and environmental adaptation are partially regulated by epigenetic mechanisms. Plasmodium falciparum GCN5 (PfGCN5) is an epigenetic regulator that acetylates lysines and can also bind to acetylated lysine residues on histones via its bromodomain (BRD). Here, we showed that PfGCN5 was essential for parasite transmission and survival in human blood and mosquitoes. PfGCN5 regulated genes important for metabolism and development and its BRD was required at euchromatic gene promoters for their proper expression and for acetylation of the variant histone Pf H2B.Z. However, PfGCN5 was most abundant in heterochromatin and loss of the PfGCN5 BRD de-repressed heterochromatic genes and increased levels of acetylated Pf H2B.Z in heterochromatin. The PfGCN5 BRD-binding compound L-45 phenocopied deletion of the PfGCN5 BRD, identifying PfGCN5 as a promising drug target for BRD inhibitors. Thus, PfGCN5 appears to directly contribute to activating euchromatic promoters, but PfGCN5 is also critical for maintaining repressive heterochromatin structure. 

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2. MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival

   https://doi.org/10.1101/gad.350736.123  

   Hurd, Matthew; Pino, Jeffrey; Jang, Kay; Allevato, Michael M; Vorontchikhina, Marina; Ichikawa, Wataru; Zhao, Yifan; Gates, Ryan; Villalpando, Emily; Hamilton, Michael J; et al (October 2023, Genes & Development)

   The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities. 

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3. Not all Is SET for Methylation: Evolution of Eukaryotic Protein Methyltransferases

   https://doi.org/10.1007/978-1-0716-2481-4_1  

   Erlendson AA; Freitag M (June 2022, Methods in molecular biology)

   Margueron R; Holoch D (Ed.)

   Dynamic posttranslational modifications to canonical histones that constitute the nucleosome (H2A, H2B, H3, and H4) control all aspects of enzymatic transactions with DNA. Histone methylation has been studied heavily for the past 20 years, and our mechanistic understanding of the control and function of individual methylation events on specific histone arginine and lysine residues has been greatly improved over the past decade, driven by excellent new tools and methods. Here, we will summarize what is known about the distribution and some of the functions of protein methyltransferases from all major eukaryotic supergroups. The main conclusion is that protein, and specifically histone, methylation is an ancient process. Many taxa in all supergroups have lost some subfamilies of both protein arginine methyltransferases (PRMT) and the heavily studied SET domain lysine methyltransferases (KMT). Over time, novel subfamilies, especially of SET domain proteins, arose. We use the interactions between H3K27 and H3K36 methylation as one example for the complex circuitry of histone modifications that make up the “histone code,” and we discuss one recent example (Paramecium Ezl1) for how extant enzymes that may resemble more ancient SET domain KMTs are able to modify two lysine residues that have divergent functions in plants, fungi, and animals. Complexity of SET domain KMT function in the well-studied plant and animal lineages arose not only by gene duplication but also acquisition of novel DNA- and histone-binding domains in certain subfamilies. 

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4. Pseudomonas syringae effector HopZ3 suppresses the bacterial AvrPto1– tomato PTO immune complex via acetylation

   Jeleńska, J.; Lee, J.; Manning, A.J.; Wolfgeher, D.J.; Ahn, Y.; Walters-Marrah, G.; Lopez, I.E.; Garcia, L.; Sheri A. McClerklin, S.A.; Michelmore, R.W.; et al (January 2021, PLOS pathogens)

   null (Ed.)

   The plant pathogen Pseudomonas syringae secretes multiple effectors that modulate plant defenses. Some effectors trigger defenses due to specific recognition by plant immune complexes, whereas others can suppress the resulting immune responses. The HopZ3 effector of P. syringae pv. syringae B728a (PsyB728a) is an acetyltransferase that modifies not only components of plant immune complexes, but also the Psy effectors that activate these complexes. In Arabidopsis, HopZ3 acetylates the host RPM1 complex and the Psy effectors AvrRpm1 and AvrB3. This study focuses on the role of HopZ3 during tomato infection. In Psy-resistant tomato, the main immune complex includes PRF and PTO, a RIPK-family kinase that recognizes the AvrPto effector. HopZ3 acts as avirulence factor on tomato by suppressing AvrPto1Psy-triggered immunity. HopZ3acetylates AvrPto1Psy and the host proteins PTO, SlRIPK and SlRIN4s. Biochemical reconstruction and site-directed mutagenesis experiments suggest that acetylation acts in multiple ways to suppress immune signaling in tomato. First, acetylation disrupts the critical AvrPto1Psy-PTO interaction needed to initiate the immune response. Unmodified residues at the binding interface of both proteins and at other residues needed for binding are acetylated. Second, acetylation occurs at residues important for AvrPto1Psy function but not for binding to PTO. Finally, acetylation reduces specific phosphorylations needed for promoting the immune-inducing activity of HopZ3’s targets such as AvrPto1Psy and PTO. In some cases, acetylation competes with phosphorylation. HopZ3-mediated acetylation suppresses the kinase activity of SlRIPK and the phosphorylation of its SlRIN4 substrate previously implicated in PTO-signaling. Thus, HopZ3 disrupts the functions of multiple immune components and the effectors that trigger them, leading to increased susceptibility to infection. Finally, mass 44 spectrometry used to map specific acetylated residues confirmed HopZ3’s unusual capacity to modify histidine in addition to serine, threonine and lysine residues. 

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5. PBRM1 bromodomains associate with RNA to facilitate chromatin association

   https://doi.org/10.1093/nar/gkad072  

   De Silva, Saumya M; Dhiman, Alisha; Sood, Surbhi; Mercedes, Kilsia F; Simmons, William J; Henen, Morkos A; Vögeli, Beat; Dykhuizen, Emily C; Musselman, Catherine A (February 2023, Nucleic Acids Research)

   Abstract PBRM1 is a subunit of the PBAF chromatin remodeling complex, which is mutated in 40–50% of clear cell renal cell carcinoma patients. It is thought to largely function as a chromatin binding subunit of the PBAF complex, but the molecular mechanism underlying this activity is not fully known. PBRM1 contains six tandem bromodomains which are known to cooperate in binding of nucleosomes acetylated at histone H3 lysine 14 (H3K14ac). Here, we demonstrate that the second and fourth bromodomains from PBRM1 also bind nucleic acids, selectively associating with double stranded RNA elements. Disruption of the RNA binding pocket is found to compromise PBRM1 chromatin binding and inhibit PBRM1-mediated cellular growth effects. 

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