Characterization of Fly POLR1D Mutations in a Clinically Relevant Residue Associated with Treacher Collins Syndrome (TCS)

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R3537.


Treacher Collins Syndrome (TCS) is an extreme craniofacial disorder caused by mutations in genes important for RNA polymerase I (Pol I) transcription. Pol I is a multi-subunit complex that transcribes ribosomal DNA (rDNA) to synthesize ribosomal RNA (rRNA). Two Pol I subunits often mutated in TCS are POLR1D and POLR1C which form a heterodimer that is important for Pol I complex assembly. Using fruit flies (D. melanogaster) as a model system, we mapped a fly POLR1D mutation that displays a severe developmental arrest phenotype in a clinically relevant residue where in a TCS patient this residue is mutated from a glycine residue to a bulky, negatively charged glutamic acid residue. In the fly mutant collection, this glycine residue is mutated to a bulkier but positively charged arginine residue. We used a simple in vitro co-expression system to examine the biochemical impact of these mutations on fly and human POLR1D and POLR1C heterodimer formation in vitro. We also complement our in vitro work with a chimeric yeast (S. cerevisiae) model in vivo where together we found that in the same mutated residue, there is a defect that impacts heterodimer formation and Pol I and III complex integrity. Our results show that fly POLR1D is a suitable model system for human TCS mutants.

MeSH terms

  • Animals
  • DNA-Directed RNA Polymerases / genetics
  • Drosophila melanogaster
  • Glycine
  • Humans
  • Mandibulofacial Dysostosis* / genetics
  • Mutation
  • Phosphoproteins / genetics
  • Saccharomyces cerevisiae


  • Phosphoproteins
  • DNA-Directed RNA Polymerases
  • POLR1D protein, human
  • Glycine

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