Abstract:
:Despite rapid advances in genome engineering technologies, inserting genes into precise locations in the human genome remains an outstanding problem. It has been suggested that site-specific recombinases can be adapted towards use as transgene delivery vectors. The specificity of recombinases can be altered either with directed evolution or via fusions to modular DNA-binding domains. Unfortunately, both wild-type and altered variants often have detectable activities at off-target sites. Here we use bacterial selections to identify mutations in the dimerization surface of Cre recombinase (R32V, R32M and 303GVSdup) that improve the accuracy of recombination. The mutants are functional in bacteria, in human cells and in vitro (except for 303GVSdup, which we did not purify), and have improved selectivity against both model off-target sites and the entire E. coli genome. We propose that destabilizing binding cooperativity may be a general strategy for improving the accuracy of dimeric DNA-binding proteins.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Eroshenko N,Church GMdoi
10.1038/ncomms3509subject
Has Abstractpub_date
2013-01-01 00:00:00pages
2509issn
2041-1723pii
ncomms3509journal_volume
4pub_type
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