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

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.

The chromatin remodeler RSF1 controls centromeric histone modifications to coordinate chromosome segregation

“…7 ). Interestingly, a recent report showed that malonylation on H2A in yeasts also prevented Bub1-mediated phosphorylation and Sgo1 accumulation 45 . Thus, histone modifications at the H2A-K118 would affect the Bub1-mediated phosphorylation in both humans and yeasts but they may use different histone modifications.…”

Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism

“…The advantage of lower eukaryotes is that it is relatively simple to replace all endogenous histones with the mutated ones. For example, H2BK37E (as a K37succ mimic), H2AK119E (as a K119mal mimic), and H4K91E (as a H4K91glu mimic) mutant yeast strains were used to investigate chromatin structure changes in vivo and complemented existing in vitro data nicely (Ishiguro et al, 2018;Jing et al, 2018;Bao et al, 2019). Nevertheless, no mimic can entirely resemble the actual modification and close structural similarity of some short-chain lysine acylations such as Kac, Kpr, or Kbu makes it difficult to mimic acylations specifically Zorro Shahidian et al, 2021).…”

Acetylation & Co: an expanding repertoire of histone acylations regulates chromatin and transcription

“…Further studies indicate that crotonylation plays a role in maintaining the pluripotent state in mouse embryonic stem cells [96], assists histone replacement during spermatogenesis [87] and can reverse HIV latency [97], potentially providing a therapeutic opportunity. One recent study has suggested that malonylation of yeast H2A may lead to a chromosome segregation defect [98]. Hypersuccinylation, achieved by both the depletion of SIRT7 and succinate dehydrogenase, results in defects in DNA repair [99,100].…”