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Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated

David R McIlwain1, Qun Pan, Patrick T Reilly

  • 1Campbell Family Cancer Research Institute and Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|June 23, 2010
PubMed

Insights

The kinase Smg1 is crucial for mouse embryonic development, as its absence causes lethality. Smg1 deficiency disrupts nonsense-mediated mRNA decay (NMD), leading to widespread changes in gene expression, particularly for splice variants.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • Smg1 is a PI3K-related kinase (PIKK) involved in DNA damage response, telomere maintenance, and nonsense-mediated mRNA decay (NMD).
  • NMD degrades transcripts with premature termination codons (PTCs), a process requiring Smg1-mediated phosphorylation of Upf1.
  • The physiological role of mammalian Smg1 has remained largely unknown.

Purpose of the Study:

  • To investigate the physiological function of Smg1 in mammalian development.
  • To determine the consequences of Smg1 deficiency on the transcriptome.

Main Methods:

  • Gene-trap model to create Smg1-deficient mice.
  • High-throughput RNA sequencing (RNA-Seq) to analyze gene expression in Smg1-deficient embryonic cells.

Main Results:

  • Smg1 deficiency is lethal during mouse embryogenesis, with lethality observed at embryonic day 8.5.
  • Smg1 depletion causes significant accumulation of PTC-containing splice variants from approximately 9% of genes susceptible to NMD.
  • Affected genes include those involved in splicing, transcription, signaling, cell death, and metabolism, some not previously known to be regulated by AS-coupled NMD.

Conclusions:

  • Smg1 plays an essential role in early mouse development.
  • Loss of Smg1 function leads to widespread alterations in the mammalian transcriptome due to impaired NMD.
  • This study identifies novel roles for AS-coupled NMD in regulating diverse cellular processes.

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