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I-CreI is a natural homing endonuclease, or meganuclease, originally derived from the chloroplast of the green alga *Chlamydomonas reinhardtii*. It belongs to the LAGLIDADG family of proteins and functions as a site-specific DNA endonuclease that recognizes a long (22-base pair) target sequence. In the field of biotechnology and gene therapy, I-CreI serves as a highly versatile scaffold for the development of engineered nucleases with customized DNA-binding specificities. Companies such as Precision BioSciences have utilized the I-CreI structure to create the ARCUS platform, which involves re-engineering the protein's DNA-binding interface to recognize and cleave specific genomic sequences associated with human diseases. Unlike CRISPR-Cas9, which requires a guide RNA, I-CreI-derived nucleases are single-protein systems where DNA recognition and catalytic cleavage are integrated into a single domain, potentially offering higher specificity, a smaller genetic footprint for viral vector delivery, and the ability to perform complex gene edits such as insertions, deletions, or gene repairs.
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