Loss of Brap Results in Premature G1/S Phase Transition and Impeded Neural Progenitor Differentiation

Alison A. Lanctot, Yan Guo, Yicong Le, Brittany M. Edens, Richard S. Nowakowski, Yuanyi Feng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Cells initiate fate decisions during G1 phase by converting extracellular signals into distinctive cell cycle kinetics. The DNA replication timing is determined in G1 phase; lengthened G1 and hastened S phases correlate with increased neurogenic propensity of neural progenitor cells (NPCs), although the underlying molecular control remains elusive. Here, we report that proper G1 phase completion in NPCs requires Brap, a Ras-Erk signaling modulator with ubiquitin E3 ligase activity. We identified Skp2 and Skp2-associated SCF ubiquitin ligase as a key target of Brap-mediated polyubiquitination. Loss of Brap resulted in elevated Skp2, which increased p27Kip1 destruction, leading to G1 phase truncation and premature S phase entry. The aberrantly executed G1 in Brap-mutant NPCs, followed by hindered S phase progression and increased G2 phase arrest, which together prolonged the cell cycle, impeded neuronal differentiation and culminated in microcephaly. These findings demonstrate that neuronal differentiation is potentiated during G1 phase by Brap-directed cascade of events in cell signaling and protein turnover.

Original languageEnglish (US)
Pages (from-to)1148-1160
Number of pages13
JournalCell Reports
Volume20
Issue number5
DOIs
StatePublished - Aug 1 2017

Keywords

  • cell cycle
  • cerebral cortical neurogenesis
  • differentiation
  • G1 phase
  • G1/S transition
  • stem/progenitor
  • ubiquitination

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Loss of Brap Results in Premature G1/S Phase Transition and Impeded Neural Progenitor Differentiation'. Together they form a unique fingerprint.

Cite this