Richard Maraia and other members of the Section of Molecular and Cell Biology are interested in RNA metabolism with continued studies of the biogenesis, metabolism, genomics, and function of tRNAs. Efforts focus on their transcription termination and 3'-end formation by RNA polymerase (RNAP) III and the role of the oligo(U)-3'-OH end-stabilizing eukaryotic protein, La in their expression pathway. Another focus is on the tRNA isopentenyltransferase that creates the anticodon-loop modification, i6A37 and its role in health, disease, development and sensitivity to rapamycin, an anti-proliferative drug that simulates nutrition deficiency and to which certain pediatric cancers develop resistance. Anticodon modifications can increase the specific activity of a tRNA for decoding, more so for one codon of a synonymous pair than the other. This creates the opportunity to encode information in the redundancy component of the genetic code, referred to as secondary or auxiliary genetic information. Trying to decipher this additional layer of genetic information and how it is used during growth and development are challenging projects for investigation.
For both of the very highly conserved tRNA isopentenyltransferase and La, the human proteins can readily complement the respective gene-deletion phenotypes in fission yeast, allowing facile structure-function analyses which in some cases includes post-translational modifications, that can then be extended to human cell culture or mice. We are interested in the fact that while both La and TRIT1 are essential for early embryonic development, La is essential for growth of embryonic stem cells whereas TRIT1 is dispensable. The Section also focuses on La-related protein-4 (LARP4) which binds to, stabilizes and promotes the translation of a subset of mRNAs involved in certain stress and signaling pathways. This Section uses genetics together with biochemistry, genome-wide profiling, a variety of high throughput deep sequencing approaches as well as cell and structural biology, in model systems that include yeast, mammalian cultured cells, and gene-altered mice.
Arimbasseri, A.G., and Maraia, R.J. (2015). Mechanism of transcription termination by RNA polymerase III utilizes a nontemplate-strand sequence-specific signal element. Mol Cell 2015 Jun 18;58(6):1124-32. doi: 10.1016/j.molcel.2015.04.002. Epub 2015 May 7. PMID: 25959395
Arimbasseri AG, Kassavetis GA, Maraia RJ. Transcription. Comment on "Mechanism of eukaryotic RNA polymerase III transcription termination". Science. 2014 Aug 1;345(6196):524.doi:10.1126/science.1253783. Epub 2014 Jul 31. PMID: 25082694
Maraia RJ, Iben JR. Different types of secondary information in the genetic code. RNA. 2014 Jul;20(7):977-84. doi: 10.1261/rna.044115.113. Review. PMID: 24935971
Yarham JW, Lamichhane TN, Pyle A, Mattijssen S, Baruffini E, Bruni F, Donnini C, Vassilev A, McFarland R, Maraia RJ, Taylor RW. Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA. PLoS Genet. 2014 Jun 5;10(6):e1004424. doi: 10.1371/journal.pgen.1004424. eCollection 2014 Jun. PMID: 24901367
Iben JR, Maraia RJ. tRNA gene copy number variation in humans. Gene. 2014 Feb 25;536(2):376-84. doi: 10.1016/j.gene.2013.11.049. Epub 2013 Dec 14. PMID: 24342656
Gaidamakov S, Maximova OA, Chon H, Blewett NH, Wang H, Crawford AK, Day A, Tulchin N, Crouch RJ, Morse HC 3rd, Blitzer RD, Maraia RJ. Targeted deletion of the gene encoding the La autoantigen (Sjögren's syndrome antigen B) in B cells or the frontal brain causes extensive tissue loss. Mol Cell Biol. 2014 Jan;34(1):123-31. doi: 10.1128/MCB.01010-13. PMID: 24190965
Lamichhane TN, Mattijssen S, Maraia RJ. Human cells have a limited set of tRNA anticodon loop substrates of the tRNA isopentenyltransferase TRIT1 tumor suppressor. Mol Cell Biol. 2013 Dec;33(24):4900-8. doi: 10.1128/MCB.01041-13. Epub 2013 Oct 14. PMID: 24126054
Arimbasseri AG, Maraia RJ. Distinguishing core and holoenzyme mechanisms of transcription termination by RNA polymerase III. Mol Cell Biol. 2013 Apr;33(8):1571-81. doi: 10.1128/MCB.01733-12. Epub 2013 Feb 11. PMID: 23401852
Iben JR, Maraia RJ. tRNAomics: tRNA gene copy number variation and codon use provide bioinformatic evidence of a new anticodon:codon wobble pair in a eukaryote. RNA. 2012 Jul;18(7):1358-72. doi: 10.1261/rna.032151.111. Epub 2012 May 14. PMID: 22586155
Rijal K, Maraia RJ. RNA polymerase III mutants in TFIIFα-like C37 that cause terminator readthrough with no decrease in transcription output. Nucleic Acids Res. 2013 Jan 7;41(1):139-55. doi: 10.1093/nar/gks985. Epub 2012 Oct 23.