2019 High impact/High risk Award by the Cancer Prevention Research Institute of Texas (CPRIT)
August 21, 2019
Mechanism-based targeting of core module of the BAF complex in cancer
High Impact/High Risk
The University of Texas Health Science Center at San Antonio
Principal Investigator/Program Director
Yogesh K Gupta
In a human cell, the ATP-dependent large macromolecular assemblies such as BAF (BRG1/BRM-associated factors) complexes utilize energy from ATP hydrolysis to re-organize the three-dimensional architecture of chromatin and associated factors so that certain parts (called regulatory regions) of DNA are accessible to proteins known as transcription factors. These factors activate gene expression programs for normal and disease conditions. Normally, the expression levels and composition of BAF complexes, and transcription factors are tightly regulated to properly maintain the organization and integrity of the human genome. But in malignant cells (especially pediatric cancers), both assembly and recruitment of the BAF chromatin-modifying enzyme complexes are disrupted by mutations, deletions, and overexpression of individual subunits, causing aberrant or residual BAF complexes. In addition, the aggressiveness of childhood cancers is also linked to chromosomal translocation events where parts of two genes are fused to form a single chimeric protein. A combination of defective BAFs and their interplay with chimeric oncofusion proteins is advantageous for the proliferation and survival of several types of pediatric sarcoma cells. These chimeras are considered highly important proteins for therapeutic targeting, but so far such efforts have not been successful. Similarly, there are no drugs that can selectively inhibit or dislodge the aberrant/residual BAFs from regulatory regions of genomic DNA in pediatric cancers. Here, we will further explore important factors that we recently found as critical for the activity and assembly of this system. If successful, this proposal will inform novel approaches to abolish tumor-promoting functions of aberrant/residual BAFs.