期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：18
页码：1
DOI：10.1073/pnas.2105547118
出版社：The National Academy of Sciences of the United States of America
摘要：Hamza et al. ( 5 ) provide proof-of-principle for an exciting approach to identify small molecules with therapeutic potential that act through specific mechanisms. Using a putative DNA–protein complex trapping allele of human FEN1 , they combine a humanized yeast model with systematic genetic interaction screening to discover genetic interactions that should be recapitulated by a FEN1 inhibitor with trapping properties. In a manner analogous to the PARP inhibitor paradigm, Hamza et al. find that nuclease-dead alleles of FEN1 are synthetic lethal with homologous recombination deficiencies. They predict that humanized yeast expressing FEN1 in a recombination deficient background should be synthetic lethal with FEN1 inhibitors that cause trapping of FEN1–DNA complexes. The experimental platform can be readily extended to additional humanized yeast models of human disease genes and therapeutic targets, adding systematic generation of putative trapping alleles by deep mutational scanning. Panels of mutants can then be fed into specialized genetic interaction screens with increasingly sophisticated readouts, including fitness, morphology, protein abundance, and protein localization ( 23 ). The detailed genetic interaction profiles that result can form the basis for small molecule screens carefully honed to identify lead compounds with very specific properties.
