Mutation of histone H3 serine 86 disrupts GATA factor Ams2 expression and precise chromosome segregation in fission yeast.

Kim Kiat Lim,Eugene Guorong Yang,Tsu Soo Tan,Kwi Shan Seah,Zhe Yang,Brian W Dymock,Ee Sin Chen,Terenze Yao Rui Ong,Bingbing Ren,Yue Rong Tan

doi:10.1038/srep14064

Abstract

Eukaryotic genomes are packed into discrete units, referred to as nucleosomes, by organizing around scaffolding histone proteins. The interplay between these histones and the DNA can dynamically regulate the function of the chromosomal domain. Here, we interrogated the function of a pair of juxtaposing serine residues (S86 and S87) that reside within the histone fold of histone H3. We show that fission yeast cells expressing a mutant histone H3 disrupted at S86 and S87 (hht2-S86AS87A) exhibited unequal chromosome segregation, disrupted transcriptional silencing of centromeric chromatin, and reduced expression of Ams2, a GATA-factor that regulates localization of the centromere-specific histone H3 variant CENP-A. We found that overexpression of ams2+ could suppress the chromosome missegregation phenotype that arose in the hht2-S86AS87A mutant. We further demonstrate that centromeric localization of SpCENP-Acnp1-1 was significantly compromised in hht2-S86AS87A, suggesting synergism between histone H3 and the centromere-targeting domain of SpCENP-A. Taken together, our work presents evidence for an uncharacterized serine residue in fission yeast histone H3 that affects centromeric integrity via regulating the expression of the SpCENP-A-localizing Ams2 protein. [173/200 words]

Highlights

Residues on histone proteins are heavily decorated with post-translational modifications (PTMs)
These PTMs function to control chromatin compaction and/or to act as docking sites for other chromatin-modifying factors that host PTM-binding motifs[1,3,4]. These epigenetic mechanisms are well characterized for PTMs planted on the N-terminal domain (NTD) of histone H3, which ensure the fidelity of cellular processes important in the maintenance of genomic integrity, such as chromosome segregation, DNA damage repair, DNA replication and transcription[5,6,7,8]
New mechanistic insights have elucidated roles for several phosphorylation sites on the histone H3 NTD: phosphorylation at histone H3 Thr 3 (H3T3) recruits the Aurora kinase-containing chromosome passenger complex[9,10,11]; H3T6 phosphorylation regulates the accessibility of the H3 Lys 4 (H3K4) demethylase LSD1 to its target[12]; H3T11 phosphorylation directs the localization of the H3K4 methylating Set1/MLL complex[13]; and phosphorylation of H3 Tyr 41 (H3Y41) counteracts the binding of a human HP1 protein in leukemic cells[14]

Summary

Introduction

Residues on histone proteins are heavily decorated with post-translational modifications (PTMs). These PTMs function to control chromatin compaction and/or to act as docking sites for other chromatin-modifying factors that host PTM-binding motifs[1,3,4] These epigenetic mechanisms are well characterized for PTMs planted on the N-terminal domain (NTD) of histone H3, which ensure the fidelity of cellular processes important in the maintenance of genomic integrity, such as chromosome segregation, DNA damage repair, DNA replication and transcription[5,6,7,8]. Our studies provide a role for the uncharacterized serine residues in the histone fold domain of histone H3 in conferring genomic stability by safeguarding the fidelity of chromosome segregation

Methods

Results

Conclusion