CRISPR-Cas orthologues and variants: optimizing the repertoire, specificity and delivery of genome engineering tools

Robust and cost-effective genome editing in a diverse array of cells and model organisms is now possible thanks to the discovery of the RNA-guided endonucleases of the CRISPR-Cas system. The commonly used Cas9 of Streptococcus pyogenes shows high levels of activity but, depending on the application,...

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Vydané v:	Mammalian genome Ročník 28; číslo 7-8; s. 247 - 261
Hlavní autori:	Cebrian-Serrano, Alberto, Davies, Benjamin
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Springer US 01.08.2017 Springer Nature B.V
Predmet:	Animal Genetics and Genomics Animals Bacterial Proteins - chemistry Bacterial Proteins - genetics Bacterial Proteins - metabolism Biomedical and Life Sciences Cell Biology cost effectiveness CRISPR CRISPR-Associated Protein 9 CRISPR-Cas Systems Deoxyribonucleases, Type II Site-Specific - genetics Deoxyribonucleases, Type II Site-Specific - metabolism DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Endonucleases - chemistry Endonucleases - genetics Endonucleases - metabolism engineering Enzymes Gene Editing Gene Transfer Techniques Genetic Engineering - methods Genetic Therapy Genome editing Genomes Human Genetics Humans Life Sciences molecular weight Mutagenesis Nuclease nucleases nucleotide sequences Protein Binding Protein Interaction Domains and Motifs proteins Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Ribonucleic acid RNA RNA, Guide, CRISPR-Cas Systems Streptococcus pyogenes Substrate Specificity Target recognition Therapeutic applications virion Wild-type SpCas9 Zinc Finger Nucleases (ZFNs) Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Cas9 Orthologs Sacaan
ISSN:	0938-8990, 1432-1777, 1432-1777
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Shrnutí:	Robust and cost-effective genome editing in a diverse array of cells and model organisms is now possible thanks to the discovery of the RNA-guided endonucleases of the CRISPR-Cas system. The commonly used Cas9 of Streptococcus pyogenes shows high levels of activity but, depending on the application, has been associated with some shortcomings. Firstly, the enzyme has been shown to cause mutagenesis at genomic sequences resembling the target sequence. Secondly, the stringent requirement for a specific motif adjacent to the selected target site can limit the target range of this enzyme. Lastly, the physical size of Cas9 challenges the efficient delivery of genomic engineering tools based on this enzyme as viral particles for potential therapeutic applications. Related and parallel strategies have been employed to address these issues. Taking advantage of the wealth of structural information that is becoming available for CRISPR-Cas effector proteins, Cas9 has been redesigned by mutagenizing key residues contributing to activity and target recognition. The protein has also been shortened and redesigned into component subunits in an attempt to facilitate its efficient delivery. Furthermore, the CRISPR-Cas toolbox has been expanded by exploring the properties of Cas9 orthologues and other related effector proteins from diverse bacterial species, some of which exhibit different target site specificities and reduced molecular size. It is hoped that the improvements in accuracy, target range and efficiency of delivery will facilitate the therapeutic application of these site-specific nucleases.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23
ISSN:	0938-8990 1432-1777 1432-1777
DOI:	10.1007/s00335-017-9697-4