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Reactive oxygen species induce Cys106-mediated anti-parallel HMGB1 dimerization that protects against DNA damage

 Man Sup Kwak  ;  Woo Joong Rhee  ;  Yong Joon Lee  ;  Hee Sue Kim  ;  Young Hun Kim  ;  Min Kyung Kwon  ;  Jeon-Soo Shin 
 REDOX BIOLOGY, Vol.40 : 101858, 2021-04 
Journal Title
Issue Date
DNA Damage ; Dimerization ; HEK293 Cells ; HMGB1 Protein* / genetics ; HMGB1 Protein* / metabolism ; Humans ; Hydrogen Peroxide / toxicity ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species
Bimolecular fluorescence complementation assay ; DNA damage ; Dimerization ; Fluorescence resonance energy transfer ; HMGB1 ; Reactive oxygen species
Oxidative stress can induce covalent disulfide bond formation between protein-protein thiol groups and generate hydroxyl free radicals that damage DNA. HMGB1 is a DNA chaperone and damage-associated molecular pattern molecule. As a redox-sensitive protein, HMGB1 contains three cysteine residues: Cys23, Cys45, and Cys106. In this study, we focused on the relationship between HMGB1 dimerization and DNA stabilization under oxidative stress conditions. HMGB1 dimerization was positively modulated by CuCl2 and H2O2. Mutation of the Cys106 residue blocked dimer formation. Treatment of HEK293T cells with CuCl2 and H2O2 enhanced the oxidative self-dimerization of HMGB1, whereas this dimerization was inhibited in mutant HMGB1C106A cells. Furthermore, we performed a bimolecular fluorescence complementation assay to visualize Cys106 oxidation-induced HMGB1 dimerization in live cells exposed to oxidative stress and were able to reproduce the dimerization effect of HMGB1 in fluorescence resonance energy transfer analysis. Interestingly, dimerized HMGB1 bound to DNA with higher affinity than monomeric HMGB1. Dimerized HMGB1 protected DNA from damage due to hydroxyl free radicals and prevented cell death. In conclusion, dimerized HMGB1 may play a regulatory role in DNA stabilization under oxidative stress.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kwak, Man Sup(곽만섭) ORCID logo https://orcid.org/0000-0002-3989-3016
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
Rhee, Woo Joong(이우중) ORCID logo https://orcid.org/0000-0001-9690-0553
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