Richard J. Maraia, M.D.
Section on Molecular and Cell Biology
RNA Metabolism in Cell Biology, Growth, and Development
We are interested in how the biogenesis and metabolism pathways for tRNAs and mRNAs interact with pathways that control cell proliferation, growth, and development. We focus on RNA polymerase (Pol) III and the post-transcriptional handling of its nascent transcripts by a eukaryote-ubiquitous RNA-binding protein known as La, which, together with La-related protein-4 (LARP4), contributes to translational control and the cell’s growth capacity. La is a nucleo-cytoplasmic shuttling protein that contains multiple RNA–binding motifs and subcellular trafficking elements, that associates with noncoding (nc)RNAs and mRNAs and presumably coordinates RNA-associated activities in the nucleus and cytoplasm. In addition to its major products (tRNAs and 5S rRNA), Pol III synthesizes a few other lower abundance ncRNAs. Tumor suppressors and oncogenes deregulate Pol III transcription, contributing to increased translational capacity of cancer cells. The La protein is a target of autoantibodies prevalent in (and diagnostic of) patients with Sjögren’s syndrome, systemic lupus, and neonatal lupus, and some Pol III subunits are also targeted in related autoimmune diseases that are associated with cancer. La protein is well known to protect its newly transcribed precursor-tRNA ligands from exonucleolytic decay during processing and modification. La binds these ligands via their common UUU-OH-3'-terminal motif that is produced by transcription termination by Pol III. Our recent studies show that LARP4 protects mRNAs from decay by binding to their poly(A) 3' tail, in a polyribosome-associated manner. We strive to understand the structure-function relationship and cell biology of La’s and LARP4’s contribution to growth and development. We use genetics, cell and structural biology, and biochemistry and genome-wide approaches in model systems that include yeast, humanand mouse tissue culture cells, and gene-altered mice.
A major interest is in deciphering what we refer to as "secondary information" in the genetic code. This information derives from the choice use of synonymous codons that encode the same amino acid. This can produce a layer of information beyond that which provides the amino acid sequence of a protein. That is to say that in addition to providing the template for the sequence of a protein, the use of certain synonymous codons can also produce additional biochemical effects, which we refer to as 'secondary information." The effects can be related to ribosome pausing which can affect protein folding, or alteratons of the stability of the mRNA. Other types of secondary information can also be encoded in the choice use of synonymous codons, for example sets of mRNAs that share similar patters of synonymous codon bias are similarly sensitive to tRNAs with the same anticodon modification and exhibit similar patterns of efficiency of translation elongation. The components of the secondary information system are the tRNA pool, the tRNA modification enzymes, and the codon bias distribution among the mRNAs.
Dr. Richard Maraia, M.D. is a Senior Investigator and Head of the Section on Molecular and Cell Biology in the Intramural Research Program of the NICHD. Dr. Maraia directs a basic research program in Biochmistry, Molecular Genetics and Genomics that seeks to understand the influences of genetics, biochemistry, and cell biology on the metabolism of small noncoding RNAs and mRNAs, and how this contributes to growth and development. Of molecular interest is the structural plasticity of the human La protein and related proteins such as La-related protein-4 (LARP4) in their ability to accommodate specific binding to a variety of RNAs that differ in sequence and structure. A major interest is in the biogenesis and metabolism of transfer RNAs, the genetic adapters that translate the genetic code, and the influences of their dynamics and relative abundances and the dynamics of their activities on codon bias-driven genetic programs involved in normal growth and in response to the physiologic states of stress and disease.
Dr. Maraia received an Associate of Science degree from Kingsborough Community College (KCC) of the City University of New York (CUNY). He was awarded The KCC Dean's Scholarship to Columbia University where he was first exposed to basic research in a tRNA laboratory in 1979 and received a B.S. in the Biological Sciences. Maraia received a M.D. from the Cornell University Medical College in 1985. As a medical student, the young Dr. Maraia spent 5 months at the NIH, in a clinical genetics course and as a researcher in the Human Genetics Branch, NICHD, Headed by Michael Zasoff, M.D., Ph.D. At this time in Zasloff's lab, Maraia again worked small noncoding RNAs related to tRNA. After medical school, Maraia obtained specialty training as an Intern and Resident in Pediatrics at The New York Hospital. He was then recruited by Dr. Zasloff, NICHD as a Clinical Fellow in the Human Genetics Branch, and also trained in the Interinstitute Medical Genetics Program of the NIH, while pursuing his basic research interests in small noncoding repeat RNAs transcribed by RNA polymerase III. He was recruited as a Research Fellow to become a founding member of the newly forming Laboratory of Molecular Growth Regulation, NICHD in 1990, became a tenure track investigator in that Lab in 1992, and was tenured in 1998. Dr. Maraia's service includes ongoing Chairmanship of the NIH Regional RNA Club. He also regularly serves on the Organizing Committees of the International Biennial Conferences on RNA Polymerases I & III, the Biennial Conferences on La and Related Protein (LARP). He has also served on the Earl Stadtman Investigator Search Committees for Molecular Biology and Biochemistry (as Chair) and for RNA Biology at the NIH, and has been actively involved in recruiting tenure track investigators to the NICHD and NIH.
Arimbasseri AG, Kassavetis GA, Maraia RJ. Transcription. Comment on "Mechanism of eukaryotic RNA polymerase III transcription termination". Science. 2014;345(6196):524.
Yarham JW, Lamichhane TN, Pyle A, Mattijssen S, Baruffini E, Bruni F, Donnini C, Vassilev A, He L, Blakely EL, Griffin H, Santibanez-Koref M, Bindoff LA, Ferrero I, Chinnery PF, 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;10(6):e1004424.
Rijal K, Maraia RJ. Active Center Control of Termination by RNA Polymerase III and tRNA Gene Transcription Levels In Vivo. PLoS Genet. 2016;12(8):e1006253.
Mattijssen S, Arimbasseri AG, Iben JR, Gaidamakov S, Lee J, Hafner M, Maraia RJ. <i>LARP4</i> mRNA codon-tRNA match contributes to LARP4 activity for ribosomal protein mRNA poly(A) tail length protection. Elife. 2017;6.
Arimbasseri AG, Maraia RJ. Mechanism of Transcription Termination by RNA Polymerase III Utilizes a Non-template Strand Sequence-Specific Signal Element. Mol Cell. 2015;58(6):1124-32.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Genetics and Genomics
This page was last updated on November 5th, 2019