Naomi Genuth

All Publications

• The Discovery of Ribosome Heterogeneity and Its Implications for Gene Regulation and Organismal Life. Molecular cell Genuth, N. R., Barna, M. 2018; 71 (3): 364–74

  Abstract

  The ribosome has recently transitioned from being viewed as a passive, indiscriminate machine to a more dynamic macromolecular complex with specialized roles in the cell. Here, we discuss the historical milestones from the discovery of the ribosome itself to how this ancient machinery has gained newfound appreciation as a more regulatory participant in the central dogma of gene expression. The first emerging examples of direct changes in ribosome composition at the RNA and protein level, coupled with an increased awareness of the role individual ribosomal components play in the translation of specific mRNAs, is opening a new field of study centered on ribosome-mediated control of gene regulation. In this Perspective, we discuss our current understanding of the known functions for ribosome heterogeneity, including specialized translation of individual transcripts, and its implications for the regulation and expression of key gene regulatory networks. In addition, we suggest what the crucial next steps are to ascertain the extent of ribosome heterogeneity and specialization and its importance for regulation of the proteome within subcellular space, across different cell types, and during multi-cellular organismal development.

  View details for DOI 10.1016/j.molcel.2018.07.018

  View details for PubMedID 30075139

• Heterogeneity and specialized functions of translation machinery: from genes to organisms. Nature reviews. Genetics Genuth, N. R., Barna, M. 2018

  Abstract

  Regulation of mRNA translation offers the opportunity to diversify the expression and abundance of proteins made from individual gene products in cells, tissues and organisms. Emerging evidence has highlighted variation in the composition and activity of several large, highly conserved translation complexes as a means to differentially control gene expression. Heterogeneity and specialized functions of individual components of the ribosome and of the translation initiation factor complexes eIF3 and eIF4F, which are required for recruitment of the ribosome to the mRNA 5' untranslated region, have been identified. In this Review, we summarize the evidence for selective mRNA translation by components of these macromolecular complexes as a means to dynamically control the translation of the proteome in time and space. We further discuss the implications of this form of gene expression regulation for a growing number of human genetic disorders associated with mutations in the translation machinery.

  View details for DOI 10.1038/s41576-018-0008-z

  View details for PubMedID 29725087

• Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. Molecular cell Shi, Z., Fujii, K., Kovary, K. M., Genuth, N. R., Röst, H. L., Teruel, M. N., Barna, M. 2017

  Abstract

  Emerging studies have linked the ribosome to more selective control of gene regulation. However, an outstanding question is whether ribosome heterogeneity at the level of core ribosomal proteins (RPs) exists and enables ribosomes to preferentially translate specific mRNAs genome-wide. Here, we measured the absolute abundance of RPs in translating ribosomes and profiled transcripts that are enriched or depleted from select subsets of ribosomes within embryonic stem cells. We find that heterogeneity in RP composition endows ribosomes with differential selectivity for translating subpools of transcripts, including those controlling metabolism, cell cycle, and development. As an example, mRNAs enriched in binding to RPL10A/uL1-containing ribosomes are shown to require RPL10A/uL1 for their efficient translation. Within several of these transcripts, this level of regulation is mediated, at least in part, by internal ribosome entry sites. Together, these results reveal a critical functional link between ribosome heterogeneity and the post-transcriptional circuitry of gene expression.

  View details for DOI 10.1016/j.molcel.2017.05.021

  View details for PubMedID 28625553

• Engineering allostery TRENDS IN GENETICS Raman, S., Taylor, N., Genuth, N., Fields, S., Church, G. M. 2014; 30 (12): 521-528

  Abstract

  Allosteric proteins have great potential in synthetic biology, but our limited understanding of the molecular underpinnings of allostery has hindered the development of designer molecules, including transcription factors with new DNA-binding or ligand-binding specificities that respond appropriately to inducers. Such allosteric proteins could function as novel switches in complex circuits, metabolite sensors, or as orthogonal regulators for independent, inducible control of multiple genes. Advances in DNA synthesis and next-generation sequencing technologies have enabled the assessment of millions of mutants in a single experiment, providing new opportunities to study allostery. Using the classic LacI protein as an example, we describe a genetic selection system using a bidirectional reporter to capture mutants in both allosteric states, allowing the positions most crucial for allostery to be identified. This approach is not limited to bacterial transcription factors, and could reveal new mechanistic insights and facilitate engineering of other major classes of allosteric proteins such as nuclear receptors, two-component systems, G protein-coupled receptors, and protein kinases.

  View details for DOI 10.1016/j.tig.2014.09.004

  View details for Web of Science ID 000347499500005

  View details for PubMedID 25306102

  View details for PubMedCentralID PMC4254034