Investigation of the RNA polymerase III (pol III) system of eukaryotes including tRNA expression, processing, modification and function, was continued, focusing on transcription termination and the function of the human La antigen which is a prevelant target of autoantibodies in patients suffering from rheumatic disorders such as neonatal lupus, systemic lupus erythematosus and Sjogrens syndrome. Pol III produces small RNAs, including the 5S rRNA and tRNAs essential for protein synthesis, as well as certain virus-encoded transcripts. Pol III is a complex enzyme composed of seventeen subunits with multiple catalytic activities. Human La antigen is a regulatory phosphoprotein that has been shown to serve as a termination factor for pol III, stimulating transcription and directing the posttranscripional maturation of the transcripts, the latter of which includes end-processing, intron removal, base modification, and proper RNA folding. The La phosphoprotein interacts with pol III transcripts by recognizing their 3 terminal UUU-OH motifs (which result from transcription termination), found at the ends of all newly synthesized pol III transcripts. Nonphosphorylated La is localized in the cytoplasm where it interacts with certain cellular and viral mRNAs including HIV RNA, hepatitis C RNA. poliovirus mRNA and others. La interacts with the internal ribosome entry sites (IRES) of viral and cellular mRNAs to modulate their translation. Some viral-encoded factors, including the adenovirus E1A protein, modulate pol III activity. Poliovirus protease-3 protein cleaves the phosphorylation site and nuclear localization signals away from the body of the La antigen, leading to a mainly cytoplasmic localization that facilitates La-mediated translation of poliovirus mRNA. We are interested in the tRNA anticodon modifications that impact the codon-usage specific translation of specific mRNAs involved in growth and development. Understanding the mechanisms by which La and other pol III subunits function in RNA production pathways, and how these pathways are controlled during normal development and cellular proliferation, are major goals of this Section. We extended our focus to La-related proteins (LARPs), including human LARP4 and LARP5, mRNA-associated proteins.

Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2013
Total Cost
$1,753,641
Indirect Cost
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State
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Maraia, Richard J; Iben, James R (2014) Different types of secondary information in the genetic code. RNA 20:977-84
Yarham, John W; Lamichhane, Tek N; Pyle, Angela et al. (2014) Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA. PLoS Genet 10:e1004424
Gaidamakov, Sergei; Maximova, Olga A; Chon, Hyongi et al. (2014) Targeted deletion of the gene encoding the La autoantigen (Sjogren's syndrome antigen B) in B cells or the frontal brain causes extensive tissue loss. Mol Cell Biol 34:123-31
Iben, James R; Maraia, Richard J (2014) tRNA gene copy number variation in humans. Gene 536:376-84
Arimbasseri, Aneeshkumar G; Rijal, Keshab; Maraia, Richard J (2013) Transcription termination by the eukaryotic RNA polymerase III. Biochim Biophys Acta 1829:318-30
Rijal, Keshab; Maraia, Richard J (2013) RNA polymerase III mutants in TFIIF*-like C37 that cause terminator readthrough with no decrease in transcription output. Nucleic Acids Res 41:139-55
Roy-Engel, Astrid M; Moss, Thomas; Maraia, Richard J (2013) Meeting report for Odd Pols 2012. Gene 526:1-6
Lamichhane, Tek N; Blewett, Nathan H; Crawford, Amanda K et al. (2013) Lack of tRNA modification isopentenyl-A37 alters mRNA decoding and causes metabolic deficiencies in fission yeast. Mol Cell Biol 33:2918-29
Arimbasseri, Aneeshkumar G; Maraia, Richard J (2013) Distinguishing core and holoenzyme mechanisms of transcription termination by RNA polymerase III. Mol Cell Biol 33:1571-81
Nagarajavel, V; Iben, James R; Howard, Bruce H et al. (2013) Global 'bootprinting' reveals the elastic architecture of the yeast TFIIIB-TFIIIC transcription complex in vivo. Nucleic Acids Res :

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