An E3 Ubiquitin Ligase Prevents Ectopic Localization of the Centromeric Histone H3 Variant via the Centromere Targeting Domain

Mol Cell. 2010 Nov 12;40(3):455-64. doi: 10.1016/j.molcel.2010.09.025.

Abstract

Proper centromere function is critical to maintain genomic stability and to prevent aneuploidy, a hallmark of tumors and birth defects. A conserved feature of all eukaryotic centromeres is an essential histone H3 variant called CENP-A that requires a centromere targeting domain (CATD) for its localization. Although proteolysis prevents CENP-A from mislocalizing to euchromatin, regulatory factors have not been identified. Here, we identify an E3 ubiquitin ligase called Psh1 that leads to the degradation of Cse4, the budding yeast CENP-A homolog. Cse4 overexpression is toxic to psh1Δ cells and results in euchromatic localization. Strikingly, the Cse4 CATD is a key regulator of its stability and helps Psh1 discriminate Cse4 from histone H3. Taken together, we propose that the CATD has a previously unknown role in maintaining the exclusive localization of Cse4 by preventing its mislocalization to euchromatin via Psh1-mediated degradation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Centromere / metabolism*
  • Chromosomal Proteins, Non-Histone / chemistry*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Euchromatin / metabolism
  • Histones / metabolism*
  • Molecular Sequence Data
  • Mutation / genetics
  • Peptide Elongation Factors / chemistry
  • Peptide Elongation Factors / metabolism*
  • Protein Binding
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Protein Stability
  • Protein Structure, Tertiary
  • Protein Transport
  • Saccharomyces cerevisiae / cytology*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • CSE4 protein, S cerevisiae
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Euchromatin
  • Histones
  • Peptide Elongation Factors
  • Protein Isoforms
  • Saccharomyces cerevisiae Proteins
  • Psh1 protein, S cerevisiae
  • Ubiquitin-Protein Ligases