Fidelity of histone gene regulation is obligatory for genome replication and stability

Prachi N. Ghule, Rong Lin Xie, Ricardo Medina, Jennifer L. Colby, Stephen N. Jones, Jane B. Lian, Janet L. Stein, Andre J. van Wijnen, Gary S. Stein

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Fidelity of chromatin organization is crucial for normal cell cycle progression, and perturbations in packaging of DNA may predispose to transformation. Histone H4 protein is the most highly conserved chromatin protein, required for nucleosome assembly, with multiple histone H4 gene copies encoding identical protein. There is a long-standing recognition of the linkage of histone gene expression and DNA replication. A fundamental and unresolved question is the mechanism that couples histone biosynthesis with DNA replication and fidelity of cell cycle control. Here, we conditionally ablated the obligatory histone H4 transcription factor HINFP to cause depletion of histone H4 in mammalian cells. Deregulation of histone H4 results in catastrophic cellular and molecular defects that lead to genomic instability. Histone H4 depletion increases nucleosome spacing, impedes DNA synthesis, alters chromosome complement, and creates replicative stress. Our study provides functional evidence that the tight coupling between DNA replication and histone synthesis is reciprocal.

Original languageEnglish (US)
Pages (from-to)2650-2659
Number of pages10
JournalMolecular and cellular biology
Volume34
Issue number14
DOIs
StatePublished - Jul 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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