Systematic drug profiling across BAF complex perturbations reveals distinct dependencies

Abstract

Chromatin remodeling by BAF complexes regulates access to DNA with implications in transcription, replication and the sensing and repair of DNA lesions, processes that are closely coupled to cell growth control. BAF complexes exist in three major subtypes each composed of a unique subset of about a dozen subunits. While for individual BAF subunits direct functions in DNA repair and cell growth have been described, we lack a more systematic interrogation of BAF perturbation and its implications in these processes. To fill this need, we subjected an isogenic BAF knockout collection to treatment with diverse genotoxic and cytotoxic compounds quantifying proliferation, cell cycle phase distributions, cell fate decisions, DNA double-strand break signaling, and transcriptional responses. The screen uncovered vulnerabilities of selected BAF-deficient cells to MEK and EGFR pathway inhibition, as well as unexpected resistance toward checkpoint inhibitors and certain DNA-damaging agents. Notably, loss of distinct ARID paralogs produced markedly divergent phenotypes, indicating limited functional redundancy and subtype-specific contributions to genome stability and cell cycle regulation. Collectively, these results provide a comparative resource linking BAF complex composition to genotoxic and cytotoxic stress responses, highlighting candidate synthetic-lethal interactions and generating hypotheses for mechanistic studies of BAF complexes in genome maintenance and cell growth control.