Malonylation of histone H2A at lysine 119 inhibits Bub1-dependent H2A phosphorylation and chromosomal localization of shugoshin proteins

Sci Rep. 2018 May 16;8(1):7671. doi: 10.1038/s41598-018-26114-z.

Abstract

Post-translational modifications of histones, such as acetylation and phosphorylation, are highly conserved in eukaryotes and their combination enables precise regulation of many cellular functions. Recent studies using mass spectrometry have revealed various non-acetyl acylations in histones, including malonylation and succinylation, which change the positive charge of lysine into a negative one. However, the molecular function of histone malonylation or succinylation is poorly understood. Here, we discovered the functions of malonylation in histone H2A at lysine 119 (H2A-K119) in chromosome segregation during mitosis and meiosis. Analyses of H2A-K119 mutants in Saccharomyces cerevisiae and Schizosaccharomyces pombe showed that anionic mutations, specifically to aspartate (K119D) and glutamate (K119E), showed mis-segregation of the chromosomes and sensitivity to microtubule-destabilizing reagents in mitosis and meiosis. We found that the chromosomal localization of shugoshin proteins, which depends on Bub1-catalyzed phosphorylation of H2A at serine 121 (H2A-S121), was significantly reduced in the H2A-K119D and the H2A-K119E mutants. Biochemical analyses using K119-unmodified or -malonylated H2A-C-tail peptides showed that H2A-K119 malonylation inhibited the interaction between Bub1 and H2A, leading to a decrease in Bub1-dependent H2A-S121 phosphorylation. Our results indicate a novel crosstalk between lysine malonylation and serine/threonine phosphorylation, which may be important for fine-tuning chromatin functions such as chromosome segregation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Centromere
  • Chromosomal Instability
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosome Segregation*
  • Chromosomes, Fungal / genetics
  • Histones / chemistry*
  • Lysine / chemistry*
  • Malonates / chemistry*
  • Mutation
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / growth & development
  • Schizosaccharomyces / metabolism*
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Sequence Homology

Substances

  • Chromosomal Proteins, Non-Histone
  • Histones
  • Malonates
  • Schizosaccharomyces pombe Proteins
  • Sgo1 protein, S pombe
  • Bub1 protein, S pombe
  • Protein Serine-Threonine Kinases
  • Lysine