Normal & Disease-Associated RNA Decay
January 16, 2014
Lynne E. Maquat, Ph.D., the J. Lowell Orbison Endowed Chair and Professor in the Department of Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry, was named the 2014 Athena Award winner today at a special luncheon at the Rochester Riverside Convention Center. The award, presented annually by the Women's Council of the Rochester Business Alliance, recognizes women who excel in their professions, give back to their communities and mentor other women for leadership roles.
Maquat is an internationally recognized expert in the field of RNA biology in which she works to discover new cellular pathways and clues to the molecular basis of human disease. She is the Founding Director of the University's Center for RNA Biology and in 2011 received one of the highest honors possible for any scientist - election to the National Academy of Sciences. In addition, having spent her career advocating for young women in the sciences, Maquat founded the University of Rochester Graduate Women in Science Program (GWIS) in 2003. Elected for her exceptional research, which has been published in more than 110 peer reviewed scientific journals, Maquat is one of only three faculty members from the University of Rochester Medical Center who have been appointed to the Academy and the only woman.
The Athena award program was founded in 1982 to recognize and honor the achievements of outstanding female leaders and introduced to Rochester in 1987. This year, Maquat was one of thirteen women chosen as finalists by the Rochester Women's Council for their professional excellence, community service and active and generous assistance in helping other women develop leadership skills.
The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex.
Half of the research in my lab focuses on NMD, which likely evolved to safeguard cells from potentially deleterious proteins produced as a consequence of routine mistakes in gene expression. In mammalian cells, these mistakes include inaccuracies in transcription initiation or pre-mRNA splicing, and ineffective somatic DNA rearrangements of the type that characterize the immunoglobulin and T-cell receptor genes. These mistakes often result in mRNAs having reading frames upstream of the usual reading frame, frameshift mutations that generate nonsense codons, or nonsense mutations. NMD also down-regulates a number of naturally occurring transcripts in mechanisms that maintain cellular homeostasis, including some selenoprotein mRNAs and alternatively spliced transcripts.
Recently, we tracked single mRNA molecules within cells in collaboration with Rob Singer's lab to verify that NMD indeed occurs on the cytoplasmic side of the nuclear envelope, with a half-life of less than one minute once the mRNA is in the cytoplasm. We have also characterized how newly synthesized mRNAs are remodeled during the pioneer round of translation and during the process of mRNA decay.
The other half of our research focuses on a mechanistically related pathway called Staufen1(STAU1)-mediated mRNA decay (SMD), or other pathways that are mediated by the double-stranded RNA-binding protein STAU1. SMD degrades mRNAs that harbor a STAU1-binding site in their 3'-untranslated regions (3'UTRs). Remarkably, depending on the particular mRNA, SBSs can be formed by (i) intramolecular base-pairing within a 3'UTR or (ii) intermolecular base-pairing between an mRNA 3'UTR and a long non-coding RNA (lncRNAs) or between an mRNA 3'UTR and another mRNA 3'UTR. Intermolecular base-pairing between an mRNA 3'UTR and a lncRNA or between two different mRNA 3'UTRs occurs via partially complementary Alu elements, thus describing new functions for these short interspersed elements (SINEs). We have shown the importance of SMD to myogenesis, keratinocyte motility, and the migration and invasion of human pancreatic adenocarcinoma cells.
Like microRNAs, more than one lncRNA or mRNA can target a single mRNA, and a single lncRNA can target more than one mRNA. Only those strands of a mRNA-lncRNA or mRNA-mRNA duplex that are translated are subject to SMD, explaining why we have yet to detect a lncRNA targeted for SMD. We have named these lncRNAs
½-sbsRNAs since they constitute one strand of an SBS. Notably, the STAU2 paralog of STAU1 also functions in SMD and, like STAU1, can homodimerize as well as form heterodimers with STAU1. In fact, homo- and hetero-multimers may exist. We have determined the X-ray crystal structure of a dimerization interface, which involves interactions between a new motif, which we have named the STAU-swapping motif, a degenerate RNA-binding domain. Remarkably, we have found that B SINES in mouse, which evolved independently of human Alu elements, also populate mRNA 3'UTRs and lncRNAs and can likewise base-pair to form SBSs and trigger SMD.
In other studies, we have found that STAU1 binding to 3'UTR inverted Alu elements competes with binding of the largely nuclear paraspeckle protein p54nrb and largely cytoplasmic protein kinase R (PKR) to mediate, respectively, the nuclear export and cytoplasmic translation of a number of mRNAs that contain these elements. Thus, STAU1 binding to 3'UTR inverted Alu elements, like removal of these elements by alternative RNA 3’-end cleavage and polyadenylation, obviates a PKR-mediated innate immune response to cytoplasmic 3'UTR inverted Alu elements.
Our on-going studies of NMD and dsRNA-binding protein-mediated RNA metabolism include computational analyses of cellular transcripts, proteomic studies of cellular RNA-binding proteins using mass spectrometry, and deep sequencing of cellular RNAs to gain insight into molecular mechanisms and how they can be attenuated for therapeutic purposes.
- Defective secretory-protein mRNAs take the RAPP. Trends Biochem Sci. 39, 154-6. (2014 Apr 01).
- Dodging two bullets with one dsRNA-binding protein. Cell Cycle. 13, 345-6. (2014 Feb 01).
- The dharma of nonsense-mediated mRNA decay in Mammalian cells. Mol Cells. 37, 1-8. (2014 Jan 30).