Analysis of Treacher Collins syndrome 4-associated mutations in Schizosaccharomyces pombe.

Treacher Collins syndrome (TCS) is a rare congenital disorder characterized by craniofacial deformities. Although mutations in several genes involved in ribosome biogenesis have been identified in patients with TCS, the molecular mechanisms underlying their effects remain poorly understood. In this study, we analyzed the effects of TCS type 4 (TCS4)-associated mutations in Schizosaccharomyces pombe by introducing R1022C or R1022S mutations into Rpa2, the second-largest subunit of RNA polymerase I (Pol I). The rpa2R1022C and rpa2R1022S mutants exhibited impaired cell growth under nutrient-rich conditions without affecting the Rpa2 protein levels. Furthermore, Pol I abnormally accumulated at the 5' region of rDNA in these mutants, resulting in defective 35S pre-rRNA biogenesis and increased sensitivity to the Pol I inhibitor BMH-21. These findings highlight the essential role of the Rpa2 residues associated with TCS4 in rRNA transcription and cell growth.