PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4

Saavedra, Francisco; Rivera, Carlos; Rivas, Elizabeth Torres; Merino, Paola; Garrido, Daniel; Hernández, Sergio; Forné, Ignasi; Vassias, Isabelle; Gurard-Levin, Zachary A.; Alfaro, Iván E.; Imhof, Axel; Almouzni, Geneviève; Loyola, Alejandra

doi:10.1093/nar/gkx775

Cited by 24 publications

(22 citation statements)

References 49 publications

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“…The multitasking protein SET is a nuclear proto-oncogene [90] and involved in apoptosis [91], transcription, nucleosome assembly and histone chaperoning [92]. SET inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT) [93]. This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

Distler

Schumann

Kesseler

et al. 2020

Cells

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Genetic disruption of synaptic proteins results in a whole variety of human neuropsychiatric disorders including intellectual disability, schizophrenia or autism spectrum disorder (ASD). In a wide range of these so-called synaptopathies a sex bias in prevalence and clinical course has been reported. Using an unbiased proteomic approach, we analyzed the proteome at the interaction site of the pre- and postsynaptic compartment, in the prefrontal cortex, hippocampus, striatum and cerebellum of male and female adult C57BL/6J mice. We were able to reveal a specific repertoire of synaptic proteins in different brain areas as it has been implied before. Additionally, we found a region-specific set of novel synaptic proteins differentially expressed between male and female individuals including the strong ASD candidates DDX3X, KMT2C, MYH10 and SET. Being the first comprehensive analysis of brain region-specific synaptic proteomes from male and female mice, our study provides crucial information on sex-specific differences in the molecular anatomy of the synapse. Our efforts should serve as a neurobiological framework to better understand the influence of sex on synapse biology in both health and disease.

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Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

Distler

Schumann

Kesseler

et al. 2020

Cells

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“…tNASP, Hsp90, Hsc70, and histone H4 elute in these fractions. Another complex composed of sNASP, HAT1, H3 and H4 elutes with a molecular weight of about 100 kDa (fractions [30][31][32]. Remarkably, in siJMJD1B derived cytosolic extracts, the complex composed of tNASP, Hsp90, Hsc70, histones H3 and H4 is shifted to a heavier molecular size fraction, comprising fractions 22-24, of about 600 kDa (Fig.…”

Section: Sijmjd1b Cells Accumulate Histones H3 and H4 At Early Steps mentioning

confidence: 89%

“…Following biosynthesis, histones H3 and H4 proceed through a maturation cascade to acquire their correct folding and to establish post-translational modifications [1, 3, 7-9, 30, 31]. In this processing pathway histones H3 and H4 are escorted by chaperones such as Hsp90, Hsc70, Hsp70; histone chaperones such as NASP, Asf1, RbAp48; and histone interacting proteins, such as PP32/ SET, HAT1, and Importin4 [1,3,30]. Newly synthesized histone H3 is monomethylated at lysine 9 (H3K9me1) during translation by the enzyme SetDB1 that is able to associate with ribosomes [28].…”

Section: Introductionmentioning

confidence: 99%

“…At chromatin, H3K9me1 can be further methylated by the Suv39H1 methyltransferase to H3K9me3, which recruits heterochromatin protein 1 (HP1) during heterochromatin replication [20,23,5 and 12 by HAT1 in a timely regulated manner. Thus, PP32/SET proteins protect acetylation of newly synthesized histone H4 to regulate the timing of acetylation [30].…”

Section: Introductionmentioning

confidence: 99%

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JMJD1B, a novel player in histone H3 and H4 processing to ensure genome stability

Saavedra

Gurard-Levin

Rojas-Villalobos

et al. 2020

Epigenetics & Chromatin

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Background: Maintaining a proper supply of soluble histones throughout the cell cycle is important to ensure chromatin and genome stability. Following their synthesis, histones undergo a series of maturation steps to prepare them for deposition onto chromatin.Results: Here, we identify the lysine demethylase JMJD1B as a novel player in the maturation cascade that contributes to regulate histone provision. We find that depletion of JMJD1B increases the protein levels of the histone chaperone tNASP leading to an accumulation of newly synthesized histones H3 and H4 at early steps of the histone maturation cascade, which perturbs chromatin assembly. Furthermore, we find a high rate of JMJD1B mutations in cancer patients, and a correlation with genomic instability. Conclusions:Our data support a role for JMJD1B in fine-tuning histone supply to maintain genome integrity, opening novel avenues for cancer therapeutics.

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“…While normal B cells predominantly contained the β isoform of SET protein, we noted in our prior work that both SETA and B protein were expressed in CLL and NHL cells (Christensen et al , ). SETA and SETB are both capable of inhibiting PP2A (Saito et al , ) activity and inhibiting nucleosome acetylation (Saavedra et al , ). We are not aware of research identifying the independent functions of the two SET isoforms or the mechanisms that regulate different SET isoform expression in CLL.…”

Section: Discussionmentioning

confidence: 99%

SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

et al. 2018

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Summary Alteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms, SETA and SETB (SETα and SETβ), significantly correlate with disease severity (overall survival and time‐to‐first‐treatment) in CLL patients. In addition, we demonstrate that relative increase of SETA to SETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications of IGHV mutated and favourable hierarchical fluorescence in situ hybridisation groups. We validate our finding by showing comparable relationships of SET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing of SET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes.

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PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4

Cited by 24 publications

References 49 publications

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

JMJD1B, a novel player in histone H3 and H4 processing to ensure genome stability

SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

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