The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

Shauna L. Houlihan, Yuanyi Feng

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders.

Original languageEnglish (US)
Article numbere03297
Pages (from-to)e03297
JournaleLife
Volume3
DOIs
StatePublished - 2014

Keywords

  • DNA damage response
  • DNA replication
  • cerebral cortex
  • chromosomes
  • cohesin
  • developmental biology
  • genes
  • heterochromatin
  • human
  • mouse
  • neurogenesis
  • stem cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation'. Together they form a unique fingerprint.

Cite this