Activity Detail
Seminar
RNA-guided nucleases: Understanding their origins and applications
Raúl Pérez Jiménez
RNA-guided nucleases (RGNs) are found in all three domains of life and have revolutionized genome engineering through their use as versatile biomolecular tools. Among the largest families of phylogenetically related RGNs are those that share a RuvC endonuclease domain, which include functionally diverse CRISPR-Cas immune systems, such as Cas9 and Cas12, as well as widely distributed transposons such as IscB, TnpB, and Fanzor. While IscB and TnpB are considered evolutionary ancestors of Cas9, Cas12, and Fanzor, current characterizations have been based primarily on sequence similarity, expression profiles, and transposon maintenance. As a result, the full biotechnological potential of ancestral RGNs remains largely untapped, offering a great opportunity for research in the forefront of biology and biotechnology. In this seminar, I will present our recent research on reconstructed ancestral forms of Cas9 and Cas12a, dating back billions of years, showing that they possess flexible molecular attributes and collateral activities that differ significantly from their modern counterparts. These findings pave the way for uncovering the evolutionary trajectories that led to the RGN diversity observed today and for translating this knowledge into next-generation genome engineering technologies. Furthermore, our finding set the stage for future research based on the hypotheses that ancestral RGNs exhibit distinct properties than modern ones; that reconstructed ancestral RGNs may reveal novel functionalities and related variants; and that these ancestral forms can be improved and applied in new genome editing applications.