Lyons Heankel, Pradhan Prashant, Prakasam Gopinath, Vashishtha Shubham, Li Xiang, Eppert Mikayla, Fornero Christy, Tcheuyap Vanina T, McGlynn Kathleen, Yu Ze, Raju Dinesh Ravindra, Koduru Prasad R, Xing Chao, Kapur Payal, Brugarolas James, Sabari Benjamin R
Laboratory of Nuclear Organization, Cecil H. and Ida Green Center for Reproductive Biology Sciences, Division of Basic Research, Department of Obstetrics and Gynecology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hematology-Oncology Division, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2025 Jul 10;188(14):3843-3862.e28. doi: 10.1016/j.cell.2025.04.002. Epub 2025 Apr 25.
Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of specificity and their relationship to function remain enigmatic. To identify rules linked to function, we leverage the genetic selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA polymerase II partitioning through a shared signature of elevated π and π-interacting residues and depletion of aliphatic residues. This signature is shared among a broad set of DNA-binding oncofusions associated with diverse cancers. We find that this signature is necessary and sufficient for RNA polymerase II partitioning, gene activation, and cancer cell phenotypes. Our results reveal that dysregulated condensate specificity is a shared molecular mechanism of diverse oncofusions, highlighting the functional role of condensate composition and the power of disease genetics in investigating relationships between condensate specificity and function.
凝聚物通过选择性地分隔生物分子来调节转录，但其特异性规则及其与功能的关系仍然是个谜。为了确定与功能相关的规则，我们利用了促进凝聚物形成的致癌融合基因的遗传选择偏向性。聚焦于驱动易位性肾细胞癌的三种最常见的致癌融合基因，我们发现它们促进凝聚物的形成，这些凝聚物通过功能获得性的RNA聚合酶II分配来激活转录，其特征是π和与π相互作用的残基升高以及脂肪族残基减少。这一特征在与多种癌症相关的广泛的DNA结合致癌融合基因中都有共享。我们发现这一特征对于RNA聚合酶II分配、基因激活和癌细胞表型是必要且充分的。我们的结果表明，失调的凝聚物特异性是多种致癌融合基因共有的分子机制，突出了凝聚物组成的功能作用以及疾病遗传学在研究凝聚物特异性与功能之间关系方面的力量。
