CRISPR-Cas systems are recently discovered RNA-based adaptive immune systems that control invasions of viruses and other mobile genetic elements in prokaryotes. CRISPR-Cas systems function by capturing short invader sequences within the CRISPR locus of the host genome, producing short crRNAs from the CRISPR, and using the crRNAs to guide Cas protein-containing effector complexes to recognize and destroy the invading nucleic acids. CRISPR-Cas based immunity is mediated by numerous and diverse Cas proteins and a given organism may possess one or more of the twelve known CRISPR-Cas modules. We know very little about how the key steps in the fascinating CRISPR-Cas immune response pathways are executed for many of the systems. Using a powerful combination of genetic, structural, and biochemical approaches, we will determine the molecular basis for how various CRISPR-Cas systems capture foreign DNA sequence within CRISPR locus memory banks to effect heritable immunity against specific invaders. We will also delineate the mechanisms by which diverse crRNA-Cas protein effector complexes selectively recognize and destroy foreign nucleic acids as a means to combat the viruses and other transgressors. The studies will provide fundamental contributions to our understanding of the range of mechanisms that have evolved to protect multitudes of prokaryotes from potentially lethal viral attack. The knowledge gained by our research will contribute directly to ongoing efforts aimed at exploiting CRISPR-Cas systems as powerful research tools (e.g. for genome editing and controlled gene expression, developing novel sequence-specific antibiotics to selectively target human pathogens (bacteria and viruses) and limiting the spread of antibiotic resistance).
A seminal discovery made only within the past decade is that bacteria and related organisms contain a dozen distinct RNA-based immune systems to protect themselves from attack by viruses. Our studies will define the molecular mechanisms that underlie these sophisticated and very novel immune systems. The information that we gain will expand and refine our ability to exploit these natural systems as powerful research tools with far- reaching biomedical applications including combatting bacteria and viruses that cause human disease and the spread of antibiotic resistance.
| Majumdar, Sonali; Terns, Michael P (2018) CRISPR RNA-guided DNA cleavage by reconstituted Type I-A immune effector complexes. Extremophiles : |
| Hatmaker, E Anne; Riley, Lauren A; O'Dell, Kaela B et al. (2018) Complete Genome Sequence of Industrial Dairy Strain Streptococcus thermophilus DGCC 7710. Genome Announc 6: |
| Shiimori, Masami; Garrett, Sandra C; Graveley, Brenton R et al. (2018) Cas4 Nucleases Define the PAM, Length, and Orientation of DNA Fragments Integrated at CRISPR Loci. Mol Cell 70:814-824.e6 |
| Terns, Michael P (2018) CRISPR-Based Technologies: Impact of RNA-Targeting Systems. Mol Cell 72:404-412 |
| Hudaiberdiev, Sanjarbek; Shmakov, Sergey; Wolf, Yuri I et al. (2017) Phylogenomics of Cas4 family nucleases. BMC Evol Biol 17:232 |
| Abreu, Eladio; Terns, Rebecca M; Terns, Michael P (2017) Visualization of Human Telomerase Localization by Fluorescence Microscopy Techniques. Methods Mol Biol 1587:113-125 |
| Majumdar, Sonali; Ligon, Marianne; Skinner, William Colby et al. (2017) Target DNA recognition and cleavage by a reconstituted Type I-G CRISPR-Cas immune effector complex. Extremophiles 21:95-107 |
| Shiimori, Masami; Garrett, Sandra C; Chambers, Dwain P et al. (2017) Role of free DNA ends and protospacer adjacent motifs for CRISPR DNA uptake in Pyrococcus furiosus. Nucleic Acids Res 45:11281-11294 |
| Ichikawa, H Travis; Cooper, John C; Lo, Leja et al. (2017) Programmable type III-A CRISPR-Cas DNA targeting modules. PLoS One 12:e0176221 |
| Elmore, Joshua R; Sheppard, Nolan F; Ramia, Nancy et al. (2016) Bipartite recognition of target RNAs activates DNA cleavage by the Type III-B CRISPR-Cas system. Genes Dev 30:447-59 |
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