BAF perturbation augments cancer cell dependence on CDK12-driven transcription elongation by RNA polymerase II

Abstract

CDK12 facilitates transcriptional elongation and processivity by RNA polymerase II (Pol II). Although it has emerged as a promising actor and target in cancer, better understanding of CDK12 gene transcription control could inform the design of novel anti-cancer strategies. Here, we identify a co-dependency between CDK12 and the BAF chromatin-remodeling complex in triple-negative breast cancer (TNBC). Genome-scale CRISPR interference screening revealed multiple BAF subunits as strong dependencies upon CDK12 inhibition. In turn, pharmacological co-targeting of CDK12 and BAF ATPase synergistically reduced the viability of multiple TNBC models. Mechanistically, the co-inhibition attenuated di-phosphorylation of the Pol II C-terminal domain at Serine-2 and Serine-5 and depleted canonical pre-mRNA 3'-end processing factors from chromatin, driving accumulation of chromatin-associated Pol II, upstream of apoptosis. Whereas BAF inhibition rapidly reduced transcription-coupled DNA accessibility, CDK12 inhibition imposed a gene length-biased transcriptional defect exacerbated by BAF deficiency. In turn, co-inhibited cells, marked by synergistic induction of MYC and repression of long cell-cycle and mitotic genes, showed a failure of DNA synthesis and mitotic entry, culminating in MYC-mediated apoptosis. Together, our findings reveal a regulatory axis in which impaired Pol II elongation creates a heightened requirement for BAF-dependent chromatin remodeling. This discovered co-dependency provides a rationale for co-targeting the CDK12-BAF axis in transcriptionally addicted cancers.