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      CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III


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          CRISPR/Cas systems constitute a widespread class of immunity systems that protect bacteria and archaea against phages and plasmids, and commonly use repeat/spacer-derived short crRNAs to silence foreign nucleic acids in a sequence-specific manner. Although the maturation of crRNAs represents a key event in CRISPR activation, the responsible endoribonucleases (CasE, Cas6, Csy4) are missing in many CRISPR/Cas subtypes. Here, differential RNA sequencing of the human pathogen Streptococcus pyogenes uncovered tracrRNA, a trans-encoded small RNA with 24 nucleotide complementarity to the repeat regions of crRNA precursor transcripts. We show that tracrRNA directs the maturation of crRNAs by the activities of the widely conserved endogenous RNase III and the CRISPR-associated Csn1 protein; all these components are essential to protect S. pyogenes against prophage-derived DNA. Our study reveals a novel pathway of small guide RNA maturation and the first example of a host factor (RNase III) required for bacterial RNA-mediated immunity against invaders.

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          Most cited references52

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          Molecular Cloning : A Laboratory Manual

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            Origins and Mechanisms of miRNAs and siRNAs.

            Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.
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              Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements.

              Prokaryotes contain short DN repeats known as CRISPR, recognizable by the regular spacing existing between the recurring units. They represent the most widely distributed family of repeats among prokaryotic genomes suggesting a biological function. The origin of the intervening sequences, at present unknown, could provide clues about their biological activities. Here we show that CRISPR spacers derive from preexisting sequences, either chromosomal or within transmissible genetic elements such as bacteriophages and conjugative plasmids. Remarkably, these extrachromosomal elements fail to infect the specific spacer-carrier strain, implying a relationship between CRISPR and immunity against targeted DNA. Bacteriophages and conjugative plasmids are involved in prokaryotic population control, evolution, and pathogenicity. All these biological traits could be influenced by the presence of specific spacers. CRISPR loci can be visualized as mosaics of a repeated unit, separated by sequences at some time present elsewhere in the cell.

                Author and article information

                31 January 2011
                31 March 2011
                30 September 2011
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                : 602-607
                [1 ]The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå Centre for Microbial Research (UCMR), Department of Molecular Biology, Umeå University, S-90187 Umeå, Sweden
                [2 ]Max F. Perutz Laboratories, University of Vienna, A-1030 Vienna, Austria
                [3 ]ZINF Research Center for Infectious Diseases, University of Würzburg, D-97080 Würzburg, Germany
                [4 ]RNA Biology Group, Institute for Molecular Infection Biology, University of Würzburg, D-97080 Würzburg, Germany
                Author notes
                Correspondence and requests for materials should be addressed to E.C. (MIMS, Umeå, Sweden; emmanuelle.charpentier@ 123456mims.umu.se ).

                Author Contributions. E.D., K.C., C.S., K.G., J.V. and E.C. designed the research; E.D., K.C., C.S., K.G., Z.A.P., Y.C. and M.E. conducted the experiments; E.D., K.C., C.S., K.G., J.V. and E.C. analyzed and interpreted the data; E.C. wrote the paper which E.D., K.C., C.S. and J.V. commented on, and supervised the project. Author information and raw data are available from E.D., K.C., C.S., J.V. and E.C.

                Author information. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.


                These authors contributed equally to this work.


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                Funded by: Austrian Science Fund FWF :
                Award ID: P 17238-B09 || FWF_



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