Abstract
RNA polymerase (Pol) III transcribes small untranslated RNAs such as 5S ribosomal RNA, transfer RNAs, and U6 small nuclear RNA. Because of the functions of these RNAs, Pol III transcription is best known for its essential contribution to RNA maturation and translation. Surprisingly, it was discovered in the last decade that various inherited mutations in genes encoding nine distinct subunits of Pol III cause tissue-specific diseases rather than a general failure of all vital functions. Mutations in the POLR3A, POLR3C, POLR3E and POLR3F subunits are associated with susceptibility to varicella zoster virus-induced encephalitis and pneumonitis. In addition, an ever-increasing number of distinct mutations in the POLR3A, POLR3B, POLR1C and POLR3K subunits cause a spectrum of neurodegenerative diseases, which includes most notably hypomyelinating leukodystrophy. Furthermore, other rare diseases are also associated with mutations in genes encoding subunits of Pol III (POLR3H, POLR3GL) and the BRF1 component of the TFIIIB transcription initiation factor. Although the causal relationship between these mutations and disease development is widely accepted, the exact molecular mechanisms underlying disease pathogenesis remain enigmatic. Here, we review the current knowledge on the functional impact of specific mutations, possible Pol III-related disease-causing mechanisms, and animal models that may help to better understand the links between Pol III mutations and disease.
Highlights
Transcription is essential to make genome-encoded information accessible, which is a basic condition for the creation of all life forms
We will focus on mutations in genes encoding subunits of the Pol III transcription system that have been associated with microbial infections or with neurodegenerative diseases, including Pol III-related hypomyelinating leukodystrophy (POLR3-HLD)
The regulatory elements upstream of the transcriptional start site (TSS) in type 3 and the promoter of the selenocysteine tRNA gene are recognized by STAF/ZNF143 and OCT1 (DSE), as well as by SNAPc/PTF (PSE), which stimulate the recruitment of TFIIIB-α to the TSS, whereupon Pol III is recruited (reviewed in Schramm and Hernandez (2002), Dumay-Odelot et al (2010); Figure 2C)
Summary
Elisabeth Lata 1†, Karine Choquet 2†, Francis Sagliocco 1, Bernard Brais 3, Geneviève Bernard 4,5,6 and Martin Teichmann 1*. Because of the functions of these RNAs, Pol III transcription is best known for its essential contribution to RNA maturation and translation. It was discovered in the last decade that various inherited mutations in genes encoding nine distinct subunits of Pol III cause tissue-specific diseases rather than a general failure of all vital functions. Other rare diseases are associated with mutations in genes encoding subunits of Pol III (POLR3H, POLR3GL) and the BRF1 component of the TFIIIB transcription initiation factor. We review the current knowledge on the functional impact of specific mutations, possible Pol III-related disease-causing mechanisms, and animal models that may help to better understand the links between Pol III mutations and disease
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