Phosphorylation and DNA binding of HJURP determine its centromeric recruitment and function in CenH3(CENP-A) loading

Cell Rep. 2014 Jul 10;8(1):190-203. doi: 10.1016/j.celrep.2014.06.002. Epub 2014 Jul 4.

Abstract

Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3(CENP-A) deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3(CENP-A) at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3(CENP-A) deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3(CENP-A) loading.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Autoantigens / metabolism*
  • Binding Sites
  • Cell Cycle
  • Cell Line, Tumor
  • Centromere / metabolism*
  • Centromere Protein A
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding

Substances

  • Autoantigens
  • CENPA protein, human
  • Centromere Protein A
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • HJURP protein, human
  • DNA