Convergent Total Synthesis of Histone H2B Protein with Site-Specific Ubiquitination at Lys120

Histone H2B Lys120 mono-ubiquitylation (H2BK120Ub) plays an important role in regulating gene expression and diverse nuclear processes. For biochemical and biophysical studies of this dynamic post-translational modification, access to homogeneous and workable amount of H2BK120Ub is obligatory. Here we report a new strategy for the convergent total chemical synthesis of homogenous histone H2BK120Ub on multi-milligram scale through the combination of hydrazide-based native chemical ligation and acid-cleavable auxiliary-mediated ligation of peptide hydrazides. The synthetic H2BK120Ub could be efficiently incorporated into nucleosomes, which may provide valuable materials for the biochemical and structural studies of nucleosome complexes involving H2BK120Ub.