Stella preserves maternal chromosome integrity by inhibiting 5hmC-induced γH2AX accumulation

EMBO Rep. 2015 May;16(5):582-9. doi: 10.15252/embr.201439427. Epub 2015 Feb 17.

Abstract

In the mouse zygote, Stella/PGC7 protects 5-methylcytosine (5mC) of the maternal genome from Tet3-mediated oxidation to 5-hydroxymethylcytosine (5hmC). Although ablation of Stella causes early embryonic lethality, the underlying molecular mechanisms remain unknown. In this study, we report impaired DNA replication and abnormal chromosome segregation (ACS) of maternal chromosomes in Stella-null embryos. In addition, phosphorylation of H2AX (γH2AX), which has been reported to inhibit DNA replication, accumulates in the maternal chromatin of Stella-null zygotes in a Tet3-dependent manner. Cell culture assays verified that ectopic appearance of 5hmC induces abnormal accumulation of γH2AX and subsequent growth retardation. Thus, Stella protects maternal chromosomes from aberrant epigenetic modifications to ensure early embryogenesis.

Keywords: 5‐hydroxymethylcytosine; Stella; Tet3; gammaH2AX; zygote.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Animals
  • Cell Division
  • Cell Line
  • Cells, Cultured
  • Chromosomal Instability*
  • Chromosomal Proteins, Non-Histone
  • Chromosome Aberrations
  • Chromosome Segregation
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA Methylation
  • DNA Replication
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Epigenesis, Genetic
  • Female
  • Gene Knockout Techniques
  • Histones / metabolism*
  • Male
  • Mice
  • Protein Transport
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Zygote / metabolism

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Dppa3 protein, mouse
  • Histones
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • Dioxygenases
  • Tet3 protein, mouse