Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules.

ABSTRACT: Orphan cytotoxins are small molecules for which the mechanism of action (MoA) is either unknown or ambiguous. Unveiling the mechanism of these compounds may lead to useful tools for biological investigation and new therapeutic leads. In selected cases, the DNA mismatch repair-deficient colorectal cancer cell line, HCT116, has been used as a tool in forward genetic screens to identify compound-resistant mutations, which have ultimately led to target identification. To expand the utility of this approach, we engineered cancer cell lines with inducible mismatch repair deficits, thus providing temporal control over mutagenesis. By screening for compound resistance phenotypes in cells with low or high rates of mutagenesis, we increased both the specificity and sensitivity of identifying resista

SUBMITTER: Nguyen TP 

PROVIDER: S-EPMC10841267 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature