Setting molecular traps in yeast for identification of anticancer drug targets

Almost 25 y have passed since Lee Hartwell et al. (1) proposed that systematic efforts to map genetic interactions in model systems promised to accelerate identification of new anticancer drug targets that exploit the unique molecular context of tumor cells. Synthetic lethal interactions, in which mutation of a gene causes cell death only when combined with mutation in another gene, are particularly relevant to cancer cells, given their many known genetic alterations (2). The promise of this concept has since been realized in the clinic: In fact, the synthetic lethality between poly(ADP ribose) polymerase (PARP) inhibition and recombination gene deficiency (e.g., BRCA1 or BRCA2 ) has become a paradigm for personalized oncology (3) (Fig. 1 A ). Part of the effect of small-molecule PARP inhibitors is attributed to their ability to block the enzymatic activity of PARP while leaving DNA binding by PARP intact. The resulting “trapped” PARP–PARP inhibitor–DNA complex contributes to the antitumor activity of PARP inhibitors and so is thought to be a desirable property, although there are indications that trapping might also limit tolerability of PARP-inhibiting drugs (4). Nonetheless, small molecules capable of trapping their target on DNA are coveted due to the prospect of increased potency. Fig. 1. ( A ) PARP inhibitors can bind to and trap PARP on DNA, interrupting the normal PARP catalytic cycle. PARP inhibition and trapping is synthetic lethal with deficiencies in homologous recombination DNA repair genes. ( B ) Hamza et al. express an allele of human FEN1 that encodes a putative trapping version of FEN1, in the presence of the normal FEN1 gene. Systematic genetic interaction screening results in a genetic interaction profile for the trapping allele of FEN1 . ( C ) Genetic interaction screening of small molecule inhibitors of FEN1 could present two possibilities. If the small molecule traps FEN1 on DNA, then the genetic interaction profile should … [↵][1]1To whom correspondence may be addressed. Email: grant.brown{at}utoronto.ca or brenda.andrews{at}utoronto.ca. [1]: #xref-corresp-1-1

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