Histone H1 Differentially Inhibits DNA Bending by Reduced and Oxidized HMGB1 Protein

Abstract

HMGB1 protein and linker histone H1 have overlapping binding sites in the nucleosome. HMGB1 has been implicated in many DNA-dependent processes in chromatin involving binding of specific proteins, including transcription factors, to DNA sites pre-bent by HMGB1. HMGB1 can also act as an extracellular signaling molecule by promoting inflammation, tumor growth a metastasis. Many of the intra- and extracellular functions of HMGB1 depend on redox-sensitive cysteine residues of the protein. Here we report that mild oxidization of HMGB1 (and much less mutation of cysteines involved in disulphide bond formation) can severely compromise the functioning of the protein as a DNA chaperone by inhibiting its ability to unwind or bend DNA. Histone H1 (via the highly basic C-terminal domain) significantly inhibits DNA bending by the full-length HMGB1, and the inhibition is further enhanced upon oxidization of HMGB1. Interestingly, DNA bending by HMGB1 lacking the acidic C-tail (HMGB1ΔC) is much less affected by histone H1, but oxidization rendered DNA bending by HMGB1ΔC and HMGB1 equally prone for inhibition by histone H1. Possible consequences of histone H1-mediated inhibition of DNA bending by HMGB1 of different redox state for the functioning of chromatin are discussed.

The role of high‐mobility group protein box 1 in lung cancer

“…Nuclear HMGB1 Participates in DNA binding, DNA bending, gene transcription, DNA replication and repair, DNA recombination, stabilizing nucleosome, maintaining telomere, and genomic stability and regulating steroid receptor activity. 11,[17][18][19] Extracellular HMGB1 Mediates cell differentiation, inflammatory response, cell migration, tissue regeneration, angiogenesis, proliferation, cell death, and immune response. [19][20][21][22][23][25][26][27]30 Cytoplasmic HMGB1 Increases autophagy and inhibits apoptosis, regulates mitochondrial morphology and function, involves in the unconventional secretory pathway.…”

Yeast HMO1: Linker Histone Reinvented

“…Although mammalian H1 has a high affinity for reconstituted dinucleosomes compared to HMGB1, the binding of HMGB1 displaces the linker histone, perhaps aided by its preferred binding to constrained DNA conformations (121)(122)(123)(124). In vitro, an interaction between the acidic tail of HMGB1 and the linker histone H1 has also been reported, suggesting that interactions with H1 may increase the DNA binding affinity of HMGB1 by preventing interactions between the acidic tail and the HMG domains, thereby facilitating the replacement of H1 with HMGB1 (125).…”

Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

“…Moreover, C23-C45 oxidation induces a shift between helix I and helix II in the A-box domain that reduces DNA binding affinity by altering the orientation of Phe37 (52), resulting in cytoplasmic translocation. HMGB1 can also affect transcription in the nucleus, requiring rapid transition between the all-thiol-and disulfide forms of HMGB1 (53).…”