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A bacterial histone binds DNA in an unorthodox fashion

ABSTRACT: Histones are the primary building blocks of chromatin in eukaryotes and many archaea. Bacteria are thought to rely on an orthogonal set of proteins to organize their chromosomes. Several bacterial genomes do, however, encode proteins with putative histone fold domains. Whether these proteins adopt a bona fide histone fold, assemble into higher order complexes that bind DNA, and play a central role in bacterial nucleoid physiology is not known. Here, we demonstrate that histones are major and essential building blocks of chromatin in the predatory bacterium Bdellovibrio bacteriovorus and the human pathogen Leptospira interrogans and likely important in several other bacterial clades. We determine the crystal structure of the B. bacteriovorus histone (Bd0055) dimer at 1.8Å resolution to reveal that histone fold topology, handshake dimer conformation, and the RD clamp motif are conserved between bacteria, archaea, and eukaryotes. However, ostensibly minor differences, including a shorter α2 helix, a less structured α3 helix, and a more acidic surface on one side of the dimer lead to a radically divergent DNA binding mode: instead of wrapping around the outer surface of a multi-subunit histone complex, DNA forms straight fibers, encased by a sheath of tightly packed Bd0055 dimers. Our results demonstrate that bacterial histones have evolved an atypical mode of DNA binding to become integral components of chromatin in distant parts of the bacterial kingdom.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Leptospira Interrogans Serovar Manilae Archaea Escherichia Coli Bl21(de3) Bdellovibrio Bacteriovorus

SUBMITTER: Alex Montoya

LAB HEAD: Dr Pavel Shliaha

PROVIDER: PXD039405 | Pride | 2023-08-21

REPOSITORIES: Pride

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			Action	DRS
	Bdellovibrio_GCA_000196175.1_ASM19617v1_protein.fasta	Fasta
	E_coli_BL21_DE3_uniprot_proteome_16042019.fasta	Fasta
	UP000234460_uniprot_Leptospira_interrogans_serovar_Manilae_20210908.fasta	Fasta
	all_results.zip	Other
	b023p050_B_bacteriovorus_WCE1_TR01.raw	Raw

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Project description:This model is described in the article: Kinetics of histone gene expression during early development of Xenopus laevis. Koster JG, Destrée OH and Westerhoff HV. J Theor Biol. 1988 Nov 21;135(2):139-67. PMID: 3267765 Abstract: Using literature data for transcriptional and translational rate constants, gene copy numbers, DNA concentrations, and stability constants, we have calculated the expected concentrations of histones and histone mRNA during embryogenesis of Xenopus laevis. The results led us to conclude that: (i) for X. laevis the gene copy number of the histone genes is too low to ensure the synthesis of sufficient histones during very early development, inheritance from the oocyte of either histone protein or histone mRNA (but not necessarily both) is necessary; (ii) from the known storage of histones in the oocyte and the rates of histone synthesis determined by Adamson and Woodland (1977), there would be sufficient histones to structure the newly synthesized DNA up to gastrulation but not thereafter (these empirical rates of histone synthesis may be underestimates); (iii) on the other hand, the amount of H3 mRNA recently observed during early embryogenesis (Koster, 1987, Koster et al., 1988) could direct a higher and sufficient synthesis of H3 protein, also after gastrulation. We present a quantitative model that accounts both for the observed H3 mRNA concentration as a function of time during embryogenesis and for the synthesis of sufficient histones to structure the DNA throughout early embryogenesis. The model suggests that X. laevis exhibits a major (i.e. some 14-fold) reduction in transcription of histone genes approximately 11 hours after fertilization. This reduction could be due to a decrease in the number of transcribed histone genes, a decreased rate constant of transcription with continued transcription of all the histone genes, and/or a reduction in the time during the cell cycle in which histone mRNA synthesis takes place. Alternatively, the histone mRNA stability might decrease approximately 16-fold 11 hours after fertilization. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Hypoxia in stem cell niches and inner core of solid tumors contributes to cellular senescence and differentiation inhibition. It directly increases histone methylationby inhibiting the activities of O2-and α-ketoglutarate (α-KG)-dependent histone lysine demethylases. This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). This study showed that Raf activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated cleavage of H3, H2B, and H4. Hypoxia prevented H3 cleavage not by inhibiting CTSL but by increasing H3K18me3 and H3K23me3 nearby cleaved site of H3. Forced expression of cleaved H3 in IMR90 cells induced senescence even under hypoxia, suggesting that hypoxia breaks this positive feedback senescence driving circle by increasing methylated histones. The decrease in methylated histones is necessary for OIS to trigger histone clipping and SAHFs, but hypoxia maintains methylated histones to prevent both. Forced reduction of methylated histones in hypoxic cells using inhibitors of methyl-transferases makes hypoxic conditions unable to prevent OIS from inducing both histone clipping and SAHFs. Reversely forced enhancement of methylated histones in normoxic cells using inhibitors of histone demethylases protected histones from clipping during OIS but failed to block SAHFs. Altogether, the maintenance of methylated histones, especially H3K23me3 and H3K18me3, is sufficient to protect histones from clipping during OIS, but not for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other methods to inhibit SAHFs. These findings provide a novel mechanism by which hypoxia affects cell fate by increasing methylated histones that protect histones and chromatin from dramatic epigenetic changes.

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A bacterial histone binds DNA in an unorthodox fashion

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