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.
Highlights
HMGB1 is an “architectural” chromatin-associated protein, a member of the High Mobility Group (HMG2) superfamily
Reports from several laboratories provided evidence that many of the intracellular and extracellular functions of HMGB1 depend on redox-sensitive cysteine residues of the protein, reviewed in [7]
Oxidization of HMGB1 by Cu2+/O2 was fully reversible as (i) treatment of the oxidized HMGB1 protein with 10 mM DTT could reverse the electrophoretic mobility to that of the reduced protein (Fig 2A, compare lanes 2 and 3), and (ii) MALDI-TOF analysis confirmed the absence of a disulphide bond between Cys22 and Cys44 upon DTT treatment of mildly oxidized HMGB1
Summary
HMGB1 is an “architectural” chromatin-associated protein, a member of the High Mobility Group (HMG2) superfamily. The protein has been implicated in many DNA-dependent processes in chromatin, as well as in cell signaling, promotion of tumor growth and metastasis, reviewed in [1,2,3,4,5]. Association of HMGB1 is not confined to specific sites in chromatin but it is rather highly dynamic, and the protein can scan the potential binding sites and move from one chromatin site to another in a “hit and run” fashion [6]. Reports from several laboratories provided evidence that many of the intracellular and extracellular functions of HMGB1 depend on redox-sensitive cysteine residues of the protein, reviewed in [7]. Changes in the redox state of HMGB1 can PLOS ONE | DOI:10.1371/journal.pone.0138774 September 25, 2015
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