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CRISPR-Cas systems are RNA-based immune systems that control invasions of viruses and plasmids in archaea and bacteria.Prokaryotes with CRISPR-Cas immune systems capture short invader sequences within the CRISPR loci in their genomes, and small RNAs produced from the CRISPR loci (CRISPR (cr)RNAs) guide Cas proteins to recognize and degrade the invading nucleic acids.There are multiple variations of the pathway found among prokaryotes, each mediated by largely distinct components and mechanisms that we are only beginning to understand.Using the hyperthermophile Pyrococcus furiosus, we have delineated several key steps in CRISPR-Cas invader defense pathways.Evidence will be presented that P.furiosus employs an impressive arsenal of three co-existing distinct immune systems, which collectively target invaders at both the RNA and DNA levels to provide robust protection from diverse invaders.