Discovery of a Splicing Regulator Required for Cell Cycle Progression

Elena S. Suvorova, Matthew Croken, Stella Kratzer, Li Min Ting, Magnolia Conde de Felipe, Bharath Balu, Meng L. Markillie, Louis M. Weiss, Kami Kim, Michael W. White

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

In the G1 phase of the cell division cycle, eukaryotic cells prepare many of the resources necessary for a new round of growth including renewal of the transcriptional and protein synthetic capacities and building the machinery for chromosome replication. The function of G1 has an early evolutionary origin and is preserved in single and multicellular organisms, although the regulatory mechanisms conducting G1 specific functions are only understood in a few model eukaryotes. Here we describe a new G1 mutant from an ancient family of apicomplexan protozoans. Toxoplasma gondii temperature-sensitive mutant 12-109C6 conditionally arrests in the G1 phase due to a single point mutation in a novel protein containing a single RNA-recognition-motif (TgRRM1). The resulting tyrosine to asparagine amino acid change in TgRRM1 causes severe temperature instability that generates an effective null phenotype for this protein when the mutant is shifted to the restrictive temperature. Orthologs of TgRRM1 are widely conserved in diverse eukaryote lineages, and the human counterpart (RBM42) can functionally replace the missing Toxoplasma factor. Transcriptome studies demonstrate that gene expression is downregulated in the mutant at the restrictive temperature due to a severe defect in splicing that affects both cell cycle and constitutively expressed mRNAs. The interaction of TgRRM1 with factors of the tri-SNP complex (U4/U6 & U5 snRNPs) indicate this factor may be required to assemble an active spliceosome. Thus, the TgRRM1 family of proteins is an unrecognized and evolutionarily conserved class of splicing regulators. This study demonstrates investigations into diverse unicellular eukaryotes, like the Apicomplexa, have the potential to yield new insights into important mechanisms conserved across modern eukaryotic kingdoms.

Original languageEnglish (US)
Article numbere1003305
JournalPLoS Genetics
Volume9
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

eukaryotic cells
cell cycle
Cell Cycle
eukaryote
Eukaryota
mutants
Temperature
protein
Toxoplasma
G1 Phase
interphase
temperature
spliceosomes
Apicomplexa
Spliceosomes
synthetic proteins
Capacity Building
Proteins
proteins
Asparagine

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Suvorova, E. S., Croken, M., Kratzer, S., Ting, L. M., de Felipe, M. C., Balu, B., ... White, M. W. (2013). Discovery of a Splicing Regulator Required for Cell Cycle Progression. PLoS Genetics, 9(2), [e1003305]. https://doi.org/10.1371/journal.pgen.1003305

Discovery of a Splicing Regulator Required for Cell Cycle Progression. / Suvorova, Elena S.; Croken, Matthew; Kratzer, Stella; Ting, Li Min; de Felipe, Magnolia Conde; Balu, Bharath; Markillie, Meng L.; Weiss, Louis M.; Kim, Kami; White, Michael W.

In: PLoS Genetics, Vol. 9, No. 2, e1003305, 02.2013.

Research output: Contribution to journalArticle

Suvorova, ES, Croken, M, Kratzer, S, Ting, LM, de Felipe, MC, Balu, B, Markillie, ML, Weiss, LM, Kim, K & White, MW 2013, 'Discovery of a Splicing Regulator Required for Cell Cycle Progression', PLoS Genetics, vol. 9, no. 2, e1003305. https://doi.org/10.1371/journal.pgen.1003305
Suvorova ES, Croken M, Kratzer S, Ting LM, de Felipe MC, Balu B et al. Discovery of a Splicing Regulator Required for Cell Cycle Progression. PLoS Genetics. 2013 Feb;9(2). e1003305. https://doi.org/10.1371/journal.pgen.1003305
Suvorova, Elena S. ; Croken, Matthew ; Kratzer, Stella ; Ting, Li Min ; de Felipe, Magnolia Conde ; Balu, Bharath ; Markillie, Meng L. ; Weiss, Louis M. ; Kim, Kami ; White, Michael W. / Discovery of a Splicing Regulator Required for Cell Cycle Progression. In: PLoS Genetics. 2013 ; Vol. 9, No. 2.
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