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

ABSTRACT: 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.

SUBMITTER: Saavedra F

PROVIDER: S-EPMC7027290 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Saavedra Francisco F Gurard-Levin Zachary A ZA Rojas-Villalobos Camila C Vassias Isabelle I Quatrini Raquel R Almouzni Geneviève G Loyola Alejandra A

Epigenetics & chromatin 20200218 1

<h4>Background</h4>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.<h4>Results</h4>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 ...[more]

PMID: 32070414

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Project description:BACKGROUND:NASP is an essential protein in mammals that functions in histone transport pathways and maintenance of a soluble reservoir of histones H3/H4. NASP has been studied exclusively in Opisthokonta lineages where some functional diversity has been reported. In humans, growing evidence implicates NASP miss-regulation in the development of a variety of cancers. Although a comprehensive phylogenetic analysis is lacking, NASP-family proteins that possess four TPR motifs are thought to be widely distributed across eukaryotes. RESULTS:We characterize the molecular evolution of NASP by systematically identifying putative NASP orthologs across diverse eukaryotic lineages ranging from excavata to those of the crown group. We detect extensive silent divergence at the nucleotide level suggesting the presence of strong purifying selection acting at the protein level. We also observe a selection bias for high frequencies of acidic residues which we hypothesize is a consequence of their critical function(s), further indicating the role of functional constraints operating on NASP evolution. Our data indicate that TPR1 and TPR4 constitute the most rapidly evolving functional units of NASP and may account for the functional diversity observed among well characterized family members. We also show that NASP paralogs in ray-finned fish have different genomic environments with clear differences in their GC content and have undergone significant changes at the protein level suggesting functional diversification. CONCLUSION:We draw four main conclusions from this study. First, wide distribution of NASP throughout eukaryotes suggests that it was likely present in the last eukaryotic common ancestor (LECA) possibly as an important innovation in the transport of H3/H4. Second, strong purifying selection operating at the protein level has influenced the nucleotide composition of NASP genes. Further, we show that selection has acted to maintain a high frequency of functionally relevant acidic amino acids in the region that interrupts TPR2. Third, functional diversity reported among several well characterized NASP family members can be explained in terms of quickly evolving TPR1 and TPR4 motifs. Fourth, NASP fish specific paralogs have significantly diverged at the protein level with NASP2 acquiring a NNR domain.

Dataset Information

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

Publications

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

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