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PubMed2026

Linker Histone H1 Phosphorylation Promotes DNA Damage Repair during Replication Stress.

DNA replication fidelity depends on the integrity of the replication fork to prevent DNA damage and preserve genome stability. Disruptions to this process can trigger replication stress, leading to the accumulation of single-strand DNA (ssDNA) and double-strand breaks (DSBs), which drive mutagenesis and ultimately contribute to disease. While the roles of core histones and their post-translational modifications in this context have been more well-studied, far less is known about how linker histones regulate the replication stress response. Here, we demonstrate that the S-phase-phosphorylated form of the linker histone H1 (pH1) plays a key role in DNA damage repair at collapsed replication forks, both in vitro and in cells. Using phosphomimic and phosphonull H1 mutants, we show that phosphorylation enhances H1 assembly with ssDNA. Utilizing intein chemistry for the site-specific incorporation of a photocrosslinker to the C-terminus of H1, we map the direct interactors of H1. We identify phosphorylated H1 at replication forks, where it engages replication machinery and DNA damage response factors, including Histone PARylation Factor 1 (HPF1). We further demonstrate that ssDNA induces pH1-HPF1 interactions that promote liquid-like assemblies, correlating with reduced DNA damage and histone PARylation. Consistent with this role, reduction of total H1 increases cellular sensitivity to DNA damage, a phenotype that is partially rescued by reintroduction of H1.4. Together, these findings establish pH1 as a new regulator of DNA damage repair at collapsed replication forks through the controlled sequestration of repair factors.

Journal Article↗
PubMed2026

Mitotic chromosomes: from the chromosome scaffold model to condensins and physical forces.

Mitotic chromosome organization and assembly remain fundamental questions in genetics. Since the chromosome scaffold model proposed in 1977 highlighted the role of nonhistone proteins in determining chromosome shape and size, key nonhistone proteins, including condensins and topoisomerase IIα (topoIIα), have been shown to play critical roles in organizing chromosome axes and chromatin loops. Emerging evidence from biochemistry, imaging, and genomics suggests that mitotic chromosome assembly is a dynamic process driven by the interplay of condensin-mediated looping, topoIIα-dependent entanglement/disentanglement, and multiple physical forces, including electrostatic nucleosome interactions, linker histone H1, free Mg2+, and depletion attraction. In this review, we discuss how these mechanisms contribute to chromosome assembly and propose that interphase chromatin domains function as dynamic building blocks of mitotic chromosomes.

chromatin compaction↗
PubMed2026

Phosphorylation of BigH1 regulates its expression pattern and promotes embryonic development.

Metazoan genomes typically encode several linker histone variants, often expressed in a tissue- or developmental stage-specific manner. The Drosophila melanogaster genome contains only two linker histone variants: H1 is present in somatic cells, while BigH1 substitutes H1 in the germline and early embryos. In the early stages of embryogenesis, BigH1 is replaced by H1 in the chromatin of somatic cells, contributing to the initiation and maintenance of the zygotic gene expression program. Nevertheless, the molecular mechanism of this exchange and the possible functions of post-translational modifications of BigH1 in this process remain elusive. Here, we identify phosphorylation as a key post-translational regulator of BigH1 dynamics. Using proteomics and targeted mutagenesis of the endogenous BigH1 locus, we show that the loss of N-terminal phosphorylation results in persistent retention of BigH1 in somatic nuclei throughout embryogenesis, indicating a failure in BigH1 turnover. In contrast, disruption of C-terminal phosphorylation does not markedly affect BigH1 clearance but increases defects during early nuclear divisions and compromises embryonic development, particularly under suboptimal conditions. Together, these findings demonstrate that domain-specific phosphorylation differentially regulates BigH1 function, coordinating its early embryonic role with its subsequent removal from the chromatin.

BigH1↗
PubMed2025

Free energy spectroscopy reveals the mechanistic landscape of chromatin compaction.

Eukaryotic genomic DNA is repeatedly wrapped into nucleosome spools: the basic building block of chromatin. This organization regulates the physical accessibility of the genome to gene transcription, replication, and repair regulatory factors. Chromatin compaction is controlled by multivalent weak interactions, resulting in a complicated conformational landscape that remains challenging to characterize. This work reports a method for characterizing chromatin compaction, Free Energy Spectroscopy (FES), which is based on DNA nanotechnology and transmission electron microscopy. This method experimentally determines the chromatin compaction free energy landscape in terms of end-to-end distance and nucleosome stacking interactions. By deconvolving the free energy landscapes of partially and fully compact tetranucleosomes, FES revealed three separate mechanisms by which linker histones reshape the compaction energetics to condense chromatin. This study establishes FES as a method with the potential to help answer a broad range of mechanistic questions about genome and epigenome function.

DNA nanotechnology↗
PubMed1979

Experimental evidence for asymmetrical shielding of nucleosomal DNA by histones.

Electron spin resonance study of Mn (II) binding to chromatin and derivatives, including core particles, shows that Mn (II) is a good probe for testing the overall electrostatic balance of the nucleoproteic complex as well as DNA accessibility. Experimental results are in good agreement with a recent model proposed (Mirzabekov A. D. and Rich A. (1979) Proc. Natl. Acad. Sci. USA 76, 1118-1121), for the core particle, in which an asymmetrical shielding of DNA by the protein core is assumed. Furthermore, it was found that the histone H1 hinders a number of charges on the linker DNA in a proportion equal to the net positive charge of the histone itself. This result is interpreted as due to a tighter interaction between the linker DNA and the core histones in the presence of histone H1.

Animals↗
PubMed1978

Photochemical cross-linking of histones to DNA nucleosomes.

Ultraviolet (UV)-induced cross-linking was utilized in order to identify histone-DNA interacting regions in the chromatin repeating unit. Fractionated mononucleosomes which contained 185 base pairs of DNA and a full complement of the histones, including histone H1, were irradiated with light of lambda greater than 290nm in the presence of a photosensitizer. Equimolar amounts of histones H2A and H2B were found, by two independent labeling experiments, to be cross-linked to the DNA. Based on previous finding that the UV irradiation specifically cross-links residues which are in close proximity, irrespective of the nature of the amino acid side chain or the nucleotide involved, our results indicate that the four core histones are not positioned equivalently with respect to the DNA. This arrangement allows histones H2A and H2B to preferentially cross-link to the DNA. A water soluble covalent complex of DNA and histones was isolated. This complex was partially resistant to mild nuclease digestion, it exhibited a CD spectrum similar to that of chromatin, and was found to contain histone H1. These results are compatible with a model which suggests that histone H1, though anchored to the linker, is bound to the DNA at additional sites. By doing so it spans the whole length of the nucleosome and clamps together the DNA fold around the histone core.

Animals↗
PubMed1979

Urea-induced binding of histone 1 to nucleosomes lacking linker DNA.

The binding of H1 (and H5) to nucleosome core particles was demonstrated by separating mononucleosomes according to their DNA size on acrylamide gels containing high molarity urea. The presence of urea causes a redistribution of H1 so that it associates with some particles of all linker lengths, including no linker. When the urea is removed the H1 remains associated with particles of all DNA sizes if the different size classes are not mixed with each other. Therefore, urea can effect the transfer of H1 from particles with linker to particles with no linker. When nucleosomes of uniform DNA fragment length, some containing and some lacking H1, are re-electrophoresed under native conditions, they migrate as two widely separated bands. The mobilities of these variants do not depend on linker length and are identical to the mobilities of native H1-containing and H1-lacking particles. When the same collection of particles is electrophoresed in the presence of high molarity urea they migrate with a uniform mobility. These results suggest that H1-containing nucleosomes are conformationally different from H1-lacking particles, but that this difference is eliminated when histone-histone interactions are disrupted by urea.

Animals↗
PubMed1976

Differences and similarities in chromatin structure of Neurospora crassa and higher eucaryotes.

The subunit structure of Neurospora chromatin which contains a full histone complement (Goff, 1976) exhibits both differences and similarities to chromatin of higher eucaryotes. The size of the DNA per subunit is only 170 +/- 5 base pairs, as compared to 200 base pairs in higher eucaryotes. However, the internal structures of the subunits are closely related. They contain 140 base pairs of DNA that are more tightly associated with the histone core and similarly arranged on the outside of the subunit. Hence the difference in structure resides in a shorter linker region of adjacent subunits in Neurospora chromatin. This is supported by a reduced primary cutting site and a lower content of lysines in histone H1. The role of H1 and its relation to the linker region are discussed.

Animals↗
PubMed1979

The distribution of histone H1 subfractions in chromatin subunits.

Rat liver chromatin was digested with micrococcal nuclease to various extents and fractionated into nucleosomes, di and trimers of nucleosomes on an isokinetic sucrose gradient. In conditions under which degradation of linker DNA within the particles was limited, the electrophoretic analysis of the histone content showed that the overall content of H1 histone increased from nucleosomes to higher order oligomers. Moreover, the histone H1 subfractions were found unevenly distributed among the chromatin subunits, one of them, H1--3 showing most variation. A more regular distribution of these subfractions was found in subunits obtained from a more extended digestion level of chromatin. It is suggested that the H1 subfractions differ in the protection they confer upon DNA.

Animals↗
PubMed1979

Identification of suberimidate cross-linking sites of four histone sequences in H1-depleted chromatin. Histone arrangement in nucleosome core.

The arrangement of 8 histones in the nucleosome core has been investigated by identifying the sites of 4 histone sequences cross-linked with a bifunctional amino-group reagent, dimethyl suberimidate, selected from among 4 diimidoesters of various linker lengths examined. H1-depleted calf thymus chromatin was allowed to react with 14C-labeled suberimidate at pH 8.5 and 0 degrees C. The cross-linked chromatin was then digested exhaustively with trypsin. Almost all the histone fragments were released from the chromatin with 0.25 M HCl and chromatographed on several columns and on paper. Cross-linked peptides were detected by analyzing the content of radioactive suberimidoylbislysine after acid hydrolysis. The chromatographic procedure developed here showed that the whole histone fragments contained 29 mol% of the total linked reagent as suberimidoylbisylsine. The 5 finally purified cross-linked peptides were identified from the total and N-terminal amino acids of each pair of peptides separated by two-dimensional cellulose thin layer chromatography after cutting the linker by ammonolysis. Thus, intramolecular cross-linking was found between Lys-5 and Lys-9 of H2A, and Lys-34 and Lys-85 of H2B, while intermolecular cross-linking was found between Lys-24 (or 27) of H2B and Lys-74 of H2A, Lys-85 of H2B and Lys-91 of H4, and Lys-120 of H2B and Lys-115 of H3 and/or Lys-77 of H4. Most of these lysine residues are located in the DNA-binding segments of the 4 histone sequences identified previously [Kato, Y. & Iwai, K, (1977) J. Biochem. 81, 621--630]. All the 5 or 6 cross-links can be located in a heterotypic tetramer consisting of one molecule each of H2A, H2B, H3, and H4, and a model of the histone arrangement in the tetramer is proposed. Two such tetramers may compose to the histone octamer in the nucleosome core.

Amino Acids↗
PubMed1978

A nuclear protein-modifying enzyme is responsive to ordered chromatin structure.

Poly (ADP-ribose) polymerase, a nuclear protein-modifying enzyme, binds to the internucleosomal linker region of chromatin, although it modifies certain core nucleosomal histones in addition to histone H1. The activity per unit of DNA chromatin changes with the nucleosome repeat number. It reaches a maximum on chromatin of 8-10 nucleosomes in length. As the complexity of chromatin with respect to nucleosome repeat number and compactness increases, a decline and stabilization of specific activity is noted. The difference in specific activity is maintained through resedimentation and dialysis of particles. It does not appear due to differences in polymer chain length or differential degradation of poly (ADP-ribose). The data suggest a relationship between ADP-ribosylation and chromatin organization and vice versa.

Binding Sites↗
PubMed1979

Analysis of the high mobility group proteins associated with salt-soluble nucleosomes.

Two methods have recently been described for the isolation of monomer nucleosomes enriched in transcribed sequences which depend on their solubility in 0.1 M NaCl (Levy, W.B. and Dixon (1978), Nucleic Acid Res., 5, 4155-4163) or solutions containing divalent metal ions (Bloom, K.S. and Anderson, J.N. (1978), Cell, 15, 141-150). Using these procedures the proteins associated with such nucleosomes from rabbit thymus, calf liver and hen oviduct nuclei were isolated and analysed. Increased amounts of proteins HMG14 AND HMG17 and small amounts of HMG1 and HMG2 were found associated with the four core histones H2A, H2B, H3 and H4 in these nucleosomes. HMG14 and HMG17 were found to be enriched 2 - 7 fold, suggesting an involvement of these two proteins with transcribed sequences. 0.1 M NaCl-soluble monomer nucleosomes prepared by the method of Levy and Dixon were analysed by polyacrylamide gel electrophoresis and found to be composed of principally two types of particle: 1. Core particles of 145 base pairs of DNA associated with the four core histones only. 2. Nucleosomes with 160 base pairs of DNA associated with the four core histones, increased amounts of HMG14 and 17, and no H1. Small amounts of HMG1 and HMG2 are also detected. These results suggest that HMG14 and HMG17 might be interacting with the 15 base pair linker DNA. A model is presented for the structure of transcriptionally active chromatin.

Animals↗
PubMed1979

A subset of trout testis nucleosomes enriched in transcribed DNA sequences contains high mobility group proteins as major structural components.

Mononucleosomes greatly enriched in non-histone proteins were prepared by limited digestion of testis nuclei with micrococcal nuclease. Five to fifteen per cent of the chromatin was solubilized and could be separated by adjustment to 0.1 M NaCl, into a soluble fraction MN1, consisting of mononucleosomes containing the four inner histones and the small basic non-histone, H6, associated with a 140-base-pair DNA fragment. H1 was notably absent in MN1. The fraction insoluble in 0.1 M NaCl (MN2) comprised a mixture of mono-, di-, tri-, and oligosomes. MN2 monosome fraction contained the four inner histones plus H1 and lacked H6 and the length of its DNA was 170 base-pairs. Previous work had shown that limited micrococcal nuclease digestion of trout testis nuclei released a great proportion of the non-histone protein, high mobility group protein T (HMG-T). It seems likely that HMG-T is the major non-histone protein located in the linker regions of a subset of nucleosomes containing the non-histone protein H6 as a major structural component. Moreover, the presence of HMG-T renders this subset of nucleosomes very sensitive to micrococcal nuclease. Hybridization experiments were performed to demonstrate that the DNA from MN1 monosomes corresponds to a subset of the trout testis genome. This DNA subset is greatly enriched in sequences that are present in cytoplasmic RNA. Chromatin subunits enriched in their content of H6 and HMG-T could also be obtained by limited digestion of trout testis chromatin with DNase II followed by precipitation with MgCl2.

Animals↗
PubMed1979

Limited action of micrococcal nuclease on trout testis nuclei generates two mononucleosome subsets enriched in transcribed DNA sequences.

Hybridization experiments show that DNA extracted from two distinct subsets of mononucleosomes (MNI and MN2) generated by a limited action of micrococcal nuclease on trout testis nuclei is enriched approximately 7-fold in sequences that are transcribed into cytoplasmic polyadenylated RNA in trout testis cells. Both subsets of mononucleosomes contain eight core histones, but MNI also possesses one or two molecules of a small, basic, high-mobility-group (HMG) protein H6 [Levy W., B., Connor, W. & Dixon, G. H. (1979) J. Biol. Chem. 254, 609-620], bound to a DNA fragment of 140 base pairs. In contrast, MN2 contains 1 molecule of H1 but no H6, and its DNA length is somewhat longer at 140-190 base pairs. The preferential release of these two subsets of mononucleosomes is correlated with the presence of a second larger HMG protein, HMG-T, in the linker regions flanking both types of mononucleosomes. The HMG-T-containing linker regions appear to be considerably more susceptible to attack by micrococcal nuclease than H1-containing linkers. Cross-reassociation reactions between the DNA from MN1 and MN2 subsets indicate that they share a significant extent of sequence overlap but also that each subset contains specific sequences that are absent in the other subset.

Animals↗