Study Uncovers Function of Mysterious Disordered Regions of Proteins Implicated in Cancer

Cigall Kadoch, PhD

New research from Dana-Farber Cancer Institute researcher Cigall Kadoch, PhD, along with colleagues at Princeton University and Washington University in St. Louis, reveals a key role for intrinsically disordered proteins known as IDRs that are implicated in a wide range of human diseases, from cancer to neurodegeneration. Kadoch’s team studies large protein complexes called mSWI/SNF or BAF complexes that control which genes turn on and off in cells. BAF complexes are the most frequently mutated cellular entities, second only to TP53, a tumor suppressor.

Intrigued by the fact that over half of the complex mass contains IDRs, including the ARID1A/B subunits in which a high frequency of disease-causing lesions, or mutations, accumulate, the group set out to define their contributions. They found that these IDR regions lead to two important functions: first, condensation, the tight clustering of proteins in close distance to one another in the nucleus, and second, protein-protein interactions that are required for the proper positioning and activity of BAF complexes along DNA. Kadoch and colleagues show that the right interactions depend on highly specific “sequence grammars” within the protein’s IDR amino acid code, a concept broadly useful to the burgeoning area of work in this area to understand and ultimately therapeutically target biomolecular condensates and their constituents.

IDRs comprise a large percentage of the human proteome and are particularly important for nuclear proteins that govern our genomic architecture and gene expression. Their disruption is frequent in cancer. This study sheds light on the sequence-specific contributions of IDRs to the highly disease-relevant mSWI/SNF (BAF) chromatin remodeling complexes, which have become top therapeutic targets in oncology.