A base editing platform for the correction of cancer driver mutations unmasks conserved p53 transcription programs.

BACKGROUND

Understanding the role of cancer hotspot mutations is essential for unraveling mechanisms of tumorigenesis and identifying therapeutic vulnerabilities. Correcting cancer mutations with base editing is a novel, yet promising approach for investigating the biology of driver mutations.

RESULTS

Here, we present a versatile platform to investigate the functional impact of cancer hotspot mutations through adenine base editing in combination with transcriptomic profiling. Using this approach, we correct TP53 hotspot mutations in cancer cell lines derived from diverse tissues, followed by mRNA sequencing to evaluate transcriptional changes. Remarkably, correcting these mutations not only reveals the dependency on mutant allele expression but also restores highly conserved tumor-suppressive transcriptional programs, irrespective of tissue origin or co-occurring mutations, highlighting a shared p53-dependent regulatory network. Our findings demonstrate the utility of this base editing platform to systematically interrogate the functional consequences of cancer-associated mutations and their downstream effects on gene expression.

CONCLUSIONS

This work establishes a robust framework for studying the transcriptional dynamics of cancer hotspot mutations and sheds light on the conserved biological processes reinstated by p53 correction, offering potential avenues for future targeted therapies.