- A.B., 1979, Cornell University, Biochemistry.
- Ph.D., 1986, Massachusetts Institute of Technology, Biology.
- Postdoctoral research: Stanford University.
- Previous faculty appointment: Oregon Health and Science University.
Joined the department in 2007.
Currently funded by the National Institutes of Health and the National Science Foundation.
One of the principal investigators on the NSF-funded project that obtained the first genome sequence of a filamentous fungus (2003).
Chair of the Fungal Policy Committee (2001-2003)
Co-Chair of the Cellular and Molecular Mycology Gordon Conference (2002)
Steering Committee for the Fungal Genome Initiative
Serves on journal editorial boards including Eukaryotic Cell, Fungal Genetics and Biology, and Genetics.
Matthew S. Sachs
College Station, TX 77843-3258
Biological Sciences Building East
Biological Sciences Building East
Understanding the mechanisms by which upstream open reading frames (uORFs) in mRNA transcripts control gene expression is currently the major focus of my laboratory. A substantial component of this work is focused on the uORF-encoded fungal arginine attenuator peptide (AAP). The major goal of this work is to understand the mechanism by which a nascent peptide encoded by this uORF controls the movement of ribosomes on mRNA and regulates gene expression. Control mechanisms mediated by uORFs and nascent peptides exist in mammals, fungi, plants, viruses, and bacteria, but relatively little is known of the molecular details of such control. The AAP is encoded by a uORF in the 5'-leader regions of mRNAs specifying the first enzyme in fungal arginine (Arg) biosynthesis. Synthesis of the AAP rapidly reduces gene expression in response to Arg. AAP-mediated regulation is observed in vivo in both Neurospora crassa and Saccharomyces cerevisiae and in vitro, using fungal, plant and animal extracts. The nascent AAP causes the ribosome to stall when the concentration of Arg is high.
We are using biochemical and genetic approaches to examine how the AAP stalls ribosomes. Our working model for regulation is that the nascent AAP adopts a conformation in the ribosomal tunnel that, with Arg (or a closely related molecule), interferes with decoding at the ribosomal A site, or with another step crucial for elongation or termination, thus stalling the ribosome.
A second crucial aspect of regulation via the AAP is that it also controls mRNA stability in vivo. Both S. cerevisiae CPA1 and N. crassa arg‑2 mRNA levels are affected by nonsense-mediated mRNA decay (NMD). AAP-mediated stalling promotes NMD of the CPA1 mRNA. In the absence of AAP-mediated stalling, NMD of the CPA1 mRNA can also be promoted by increased ribosome occupancy of the uORF. These data support a regulatory model in which ribosome stalling at the uORF termination codon in response to Arg destabilizes CPA1 mRNA by increasing the extent of nonsense codon recognition by NMD. This link between AAP-mediated stalling and NMD provides unique opportunities for assessing the cis- and trans-acting elements that contribute to NMD.
Related work explores the functions of other uORFs whose existence was deduced by in silico methods. In collaboration with investigators at the Broad Institute and others, we examined the functions of two such uORFs that were observed to be evolutionarily conserved in three Aspergillus species. We are now evaluating the functions of Cryptococcus neoformans uORFs displaying varying levels of evolutionary conservation. Experimental study and validation of such conserved elements has lagged far behind their identification.
We have longstanding collaborations to perform large scale analyses of the N. crassa genome Our studies are now centered on systematically understanding the functions of N. crassa genes and the mechanisms that regulate them. Currently, our lab is primarily responsible for scientific (not automated) curation of N. crassa genome data housed at the Broad Institute, and therefore evaluates the quality and accuracy of the data for gene models and proposed functions. We are also developing additional resources that will be useful to curators and the community for data mining, including the implementation of full-text literature searching resources for filamentous fungi using the Textpresso application developed at Caltech.
A second aspect of our functional genomics work is that we are synthesizing N. crassa cDNA libraries to obtain full length cDNAs that will be used for sequencing to improve genome annotation. The capability to obtain and characterize such cDNA clones is important for all functional genomics efforts, particularly in intron-rich organisms, such as N. crassa, since sequencing of full-length cDNAs provides data critical for understanding mRNA structure not readily obtainable by any other methods.
- Martínez AK, Gordon E, Sengupta A, Shirole N, Klepacki D, Martinez-Garriga B, Brown LM, Benedik MJ, Yanofsky C, Mankin AS, Vazquez-Laslop N, Sachs MS & Cruz-Vera LR (2013) Interactions of the TnaC nascent peptide with rRNA in the exit tunnel enable the ribosome to respond to free tryptophan. Nucleic Acids Res 0: Full text
- Dreyfuss JM, Zucker JD, Hood HM, Ocasio LR, Sachs MS & Galagan JE (2013) Reconstruction and validation of a genome-scale metabolic model for the filamentous fungus Neurospora crassa using FARM. PLoS Comput Biol 9:e1003126 Full text
- Zhou M, Guo J, Cha J, Chae M, Chen S, Barral JM, Sachs MS & Liu Y (2013) Non-optimal codon usage affects expression, structure and function of clock protein FRQ. Nature 495:111-5 Full text
- Wei J, Zhang Y, Ivanov IP & Sachs MS (2013) The stringency of start codon selection in the filamentous fungus Neurospora crassa. J Biol Chem 288:9549-62 Full text
- Wei J, Wu C & Sachs MS (2012) The arginine attenuator peptide interferes with the ribosome peptidyl transferase center. Mol Cell Biol 32:2396-406 Full text
- Zhai B, Wu C, Wang L, Sachs MS & Lin X (2012) The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother 56:3758-66 Full text
- Wu C, Wei J, Lin PJ, Tu L, Deutsch C, Johnson AE & Sachs MS (2012) Arginine changes the conformation of the arginine attenuator peptide relative to the ribosome tunnel. J Mol Biol 416:518-33 Full text
- Loughran G, Sachs MS, Atkins JF & Ivanov IP (2012) Stringency of start codon selection modulates autoregulation of translation initiation factor eIF5. Nucleic Acids Res 40:2898-906 Full text
- Martínez AK, Shirole NH, Murakami S, Benedik MJ, Sachs MS & Cruz-Vera LR (2012) Crucial elements that maintain the interactions between the regulatory TnaC peptide and the ribosome exit tunnel responsible for Trp inhibition of ribosome function. Nucleic Acids Res 40:2247-57 Full text
- Cruz-Vera LR, Sachs MS, Squires CL & Yanofsky C (2011) Nascent polypeptide sequences that influence ribosome function. Curr Opin Microbiol 14:160-6 Full text