Details

Autor(en) / Beteiligte

• Hallberg, Line A.E.
• Thorsen, Nicoline W.
• Hartsema, Els A.
• Hägglund, Per M.
• Hawkins, Clare L.

Titel

Mapping the modification of histones by the myeloperoxidase-derived oxidant hypochlorous acid (HOCl)

Ist Teil von

• Free radical biology & medicine, 2022-11, Vol.192, p.152-164

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2022

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• Histones are critical for the packaging of nuclear DNA and chromatin assembly, which is facilitated by the high abundance of Lys and Arg residues within these proteins. These residues are also the site of a range of post-translational modifications, which influence the regulatory function of histones. Histones are also present in the extracellular environment, following release by various pathways, particularly neutrophil extracellular traps (NETs). NETs contain myeloperoxidase, which retains its enzymatic activity and produces hypochlorous acid (HOCl). This suggests that histones could be targets for HOCl under conditions where aberrant NET release is prevalent, such as chronic inflammation. In this study, we examine the reactivity of HOCl with a mixture of linker (H1) and core (H2A, H2B, H3 and H4) histones. HOCl modified the histones in a dose- and time-dependent manner, resulting in structural changes to the proteins and the formation of a range of post-translational modification products. N-Chloramines are major products following exposure of the histones to HOCl and decompose over 24 h forming Lys nitriles and carbonyls (aminoadipic semialdehydes). Chlorination and dichlorination of Tyr, but not Trp residues, is also observed. Met sulfoxide and Met sulfones are formed, though these oxidation products are also detected albeit at a lower extent, in the non-treated histones. Evidence for histone fragmentation and aggregation was also obtained. These results could have implications for the development of chronic inflammatory diseases, given the key role of Lys residues in regulating histone function. [Display omitted] •N-chloramines are major products on histones treated with hypochlorous acid (HOCl).•Histone chloramines decompose to form Lys nitriles and carbonyls.•HOCl induces chlorination of Tyr but not Trp residues on histones.•Fragmentation and aggregation of histones occurs on exposure to HOCl.•These reactions may be important in NET-associated inflammatory damage.