The Mammalian and Yeast A49 and A34 Heterodimers: Homologous but Not the Same

Abstract

Ribosomal RNA synthesis is the rate-limiting step in ribosome biogenesis. In eukaryotes, RNA polymerase I (Pol I) is responsible for transcribing the ribosomal DNA genes that reside in the nucleolus. Aberrations in Pol I activity have been linked to the development of multiple cancers and other genetic diseases. Therefore, it is key that we understand the mechanisms of Pol I transcription. Recent studies have demonstrated that there are many differences between Pol I transcription in yeast and mammals. Our goal is to highlight the similarities and differences between the polymerase-associated factors (PAFs) in yeast and mammalian cells. We focus on the PAF heterodimer A49/34 in yeast and PAF53/49 in mammals. Recent studies have demonstrated that while the structures between the yeast and mammalian orthologs are very similar, they may function differently during Pol I transcription, and their patterns of regulation are different.

The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans

“…Therefore, the findings of the three studies support and supplement each other. We also show that functional cross-species complementation of RPA49/34 subcomplexes is possible, which is in line with a conserved role in supporting initiation and elongation stages of the transcription cycle while accumulating divergent regulatory properties (103,104,105). An increased flexibility of the clamp/stalk module in hPol I is indicated by the cryo-EM reconstruction (Fig 2 ) and may explain an increased rate of incorrect nucleotide addition we observe in comparison to the yeast enzymes in vitro (Fig 2B).…”

The human RNA polymerase I structure reveals an HMG-like transcription factor docking domain specific to metazoans

“…We show that functional cross-species complementation of RPA49/34 subcomplexes is possible, which is in line with a conserved role in supporting initiation and elongation stages of the transcription cycle while accumulating divergent regulatory properties [92][93][94] . An increased flexibility of the clamp/stalk module in hPol I is indicated by the cryo-EM reconstruction (Fig.…”

PAF49: An RNA Polymerase I subunit essential for rDNA transcription and stabilization of PAF53

“…As previously mentioned, PAF49 and PAF53 act as a heterodimer and are required to support Pol I transcription and cell proliferation ( 36 , 41 , 42 , 61 , 67 ). Our study is the first to report that PAF49 is required to stabilize the levels of PAF53.…”

“…These results conflict with studies performed in yeast that report RPA34, the homolog to PAF49, is not essential for proliferation or rDNA transcription ( 31 , 32 , 48 , 49 ). Multiple studies from our laboratory and others have demonstrated that although there are similarities between the yeast and the mammalian Pol I systems ( 30 , 41 , 42 , 69 ), there are also many differences that warrant the need to study this system in mammals in order to effectively target the process of rDNA transcription in disease models where ribosome biogenesis and/or Pol I transcription is dysregulated.…”

“…We have now extended our studies to mammalian PAF49. We have found that the auxin-induced degradation of PAF49 inhibits rDNA transcription and cell division ( 42 ). Structural studies of yeast RPA34.5 demonstrated that the molecule contained an N-terminal dimerization domain and an “arm” that appears to mediate its interaction with the A135 subunit of Pol I ( 28 , 29 , 43 ).…”