Cryo-EM structures of human RNA polymerase I

Ribosomal RNA (rRNA) transcription by RNA Polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies which frequently affect craniofacial development. Here, we present a cellular and molecular mechanism to explain the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCC), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCC particulalry sensitive to rRNA synthesis defects. Underpinning these findings, NCC-specific deletion of Pol I subunits Polr1a, Polr1c, and associated factor Tcof1 in mice cell-autonomously diminishes rRNA synthesis, which causes an imbalance between rRNA and ribosomal proteins. This leads to increased ribosomal protein binding to Mdm2 and concomitantly diminished Mdm2 binding to p53. Consequently, p53 protein accumulates, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbates the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins Syndrome and Acrofacial Dysostosis Cincinnati Type. Our novel results therefore demonstrate the dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of craniofacial congenital diseases.

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Cryo-EM structures of human RNA polymerase I

Cited by 2 publications

References 109 publications

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A structural perspective of human RNA polymerase III

Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development

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