A Protein Semisynthesis-Based Strategy to Investigate the Functional Impact of Linker Histone Serine ADP-Ribosylation

Kyuto Tashiro, Jugal Mohapatra, Chad A. Brautigam, Glen Liszczak

Research output: Contribution to journalArticlepeer-review

Abstract

Recently developed chemical and enzyme-based technologies to install serine ADP-ribosylation onto synthetic peptides have enabled new approaches to study poly(ADP-ribose) polymerase (PARP) biology. Here, we establish a generalizable strategy to prepare ADP-ribosylated peptides that are compatible with N-terminal, C-terminal, and sequential protein ligation reactions. Two unique protein-assembly routes are employed to generate full-length linker histone constructs that are homogeneously ADP-ribosylated at known DNA damage-dependent modification sites. We found that serine mono-ADP-ribosylation is sufficient to alleviate linker histone-dependent chromatin compaction and that this effect is amplified by ADP-ribose chain elongation. Our work will greatly expand the scope of ADP-ribose-modified proteins that can be constructed via semisynthesis, which is rapidly emerging as a robust approach to elucidate the direct effects that site-specific serine mono- and poly-ADP-ribosylation have on protein function.

Original languageEnglish (US)
JournalACS chemical biology
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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