Richard J. Maraia, M.D.
Section on Molecular and Cell Biology
Bethesda, MD 20892-2790
RNA Metabolism in Cell Biology, Growth, and Development
We are interested in how the pathways for biogenesis and metabolism of tRNAs and mRNAs control the flow and processing of genetic information in a broad sense and during cell proliferation, growth and development. We are interested in control and regulation of three components of the genetic code primary and secondary information system, mRNAs, tRNAs, and tRNA modifications, many of the latter of which are directed to the anticodon to control wobble decoding, translation efficiency and fidelity. One focus is on tRNA synthesis by RNA polymerase (Pol) III, the post-transcriptional handling of its nascent precursor-tRNA transcripts by the eukaryote-ubiquitous RNA-binding nuclear phosphoprotein La, and posttranscriptional modifications of a subset of tRNAs by tRNA isopentenyltransferase (TRIT1) and tRNA methyltransferase (Trm1).
Although La protein is mostly nuclear it contains multiple subcellular trafficking elements and RNA–binding motifs, and associates with multiple noncoding (nc)RNAs and mRNAs presumably to coordinate certain RNA-associated activities in the nucleus and cytoplasm. Tumor suppressors and oncogenes deregulate Pol III transcription, contributing to increased translational capacity of cancer cells. The La protein is a target of autoantibodies that are 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.
The conserved activity of La protein is to bind and protect a large subset of abundant small nascent RNAs from 3' exonucleases and other factors that can divert transcripts away their maturation pathways. La binds these RNAs via their common UUU-OH-3'-terminal motif which is produced by the mechanism of their transcription termination by Pol III. This 3' end protection activity is highly relevant for nascent precursor-tRNAs, which are the most abundant products of Pol III. The pre-tRNAs are transcribed from several hundred genes that vary in sequence including the 5' leader and 3' trailer, and are susceptible to diversion to offline pathways. They undergo a multistep phase of intranuclear processing and modification prior to export to the cytoplasm for function in translation.
Another major focus is La-related protein-4 (LARP4), a cytoplasmic multimodular protein that interacts with cytoplasmic poly(A)-binding protein (PABPC1), an abundant factor involved in the general control of the translation and stability/metabolism/turnover of mRNA, as well as RACK1 (receptor for activated protein C kinase 1) a stoichiometric 40S ribosome mRNA exit channel-associated protein. Our studies have shown that LARP4 promotes translation polyribosome-associated manner and protects mRNAs from decay by opposing the degradative action of deadenylases on their poly(A) 3' tail.
In all of our studies we strive to understand the structure-function relationship, cell biology and context in growth and development. We use genetics, genomics, cell and structural biology, and biochemistry and genome-wide approaches in model systems that include yeast, human and mouse tissue culture cells, and gene-altered mice. We use and develop high-throughput sequencing methods.
A major interest is in deciphering what we refer to as "secondary information" (aka auxiliary information) in the genetic code. This secondary information refers to and 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 which is primary genetic code information. 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 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, and/or decay. The components of the secondary information system are the tRNA pool, the tRNA modification enzymes, and the codon bias distribution among mRNAs. While the primary genetic code information is universal (except for the non-universal codes in use in mitochondria and certain other organelles), secondary genetic code information can and is species-specific.
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 broadly 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) and LARP1 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 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 in 1977. At Columbia University he began basic research in a tRNA laboratory supported as a Josiah Macy Research Scholar, and received a B.S. in the Biological Sciences. Prior to beginning medical school at the Cornell University Medical College, he worked in the laboratory of Somatic Cell Geneticist, Gretchen J. Darlington, on basic aspects of tissue-specific gene-activation and continued through his first and second years. As a senior medical student, the young Dr. Maraia spent 5 months at the NIH, in a clinical genetics course and doing basic research in the Human Genetics Branch, NICHD, Headed by Michael Zasoff, M.D., Ph.D. At this time in Zasloff's lab, Maraia again worked on small noncoding RNAs related to tRNA. After being graduated from Cornell University Medical College in 1985, 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, NIH and in the Interinstitute Medical Genetics Program of the NIH, while pursuing his basic research interests in small noncoding repeat RNAs (Alu and related) transcribed by RNA polymerase III. He was then recruited by the NICHD Scientific Director, Arthur S. Levine, as a Research Fellow to join as a founding member of the newly forming Laboratory of Molecular Growth Regulation, NICHD in 1990, to be headed by Bruce H. Howard, M.D., recruited from the NCI, NIH who was also interested in Alu repetitive elements. Dr. Maraia became a tenure track investigator in that Lab in 1992, after his first site visit as an independent investigator, 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.
Mattijssen S, Iben JR, Li T, Coon SL, Maraia RJ. Single molecule poly(A) tail-seq shows LARP4 opposes deadenylation throughout mRNA lifespan with most impact on short tails. Elife. 2020;9.
Khalique A, Mattijssen S, Haddad AF, Chaudhry S, Maraia RJ. Targeting mitochondrial and cytosolic substrates of TRIT1 isopentenyltransferase: Specificity determinants and tRNA-i6A37 profiles. PLoS Genet. 2020;16(4):e1008330.
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.
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.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Genetics and Genomics
This page was last updated on September 26th, 2020