Juan A Perez-Bermejo, Oghene Efagene, William M Matern, Jeffrey K Holden, Shaheen Kabir, Glen M Chew, Gaia Andreoletti, Eniola Catton, Craig L Ennis, Angelica Garcia, Trevor L Gerstenberg, Kaisle A Hill, Aayami Jain, Kristina Krassovsky, Cassandra D Lalisan, Daniel Lord, B Joy Quejarro, Jade Sales-Lee, Meet Shah, Brian J Silva, Jason Skowronski, Yuri G Strukov, Joshua Thomas, Michael Veraz, Twaritha Vijay, Kirby A Wallace, Yue Yuan, Jane L Grogan, Beeke Wienert, Premanjali Lahiri, Sebastian Treusch, Daniel P Dever, Vanessa B Soros, James R Partridge, Kristen L Seim
Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR...
March 23, 2024: Nature Communications