Protein intrinsic disorder in genome regulation

The National Institute of General Medical Sciences awarded The University of Texas Health Science Center at San Antonio $378,000 on May 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate how intrinsically disordered proteins and regions regulate nuclear processes essential for genome stability, including transcription, RNA processing, and the DNA damage response.

Over five years through April 30, 2031, the recipient will identify sequence and structural features that influence biomolecular condensate mechanics, elucidate how intrinsically disordered region-facilitated interactions regulate factor recruitment and release, and develop advanced NMR strategies for characterizing large, disordered protein complexes in near-native contexts. Research focuses on two complementary systems: the RNA-binding protein EWS and its fusion variant EWS::FLI1, which perturbs condensate dynamics and transcriptional regulation; and the BRCA1-BARD1 heterodimer, a multifunctional DNA repair complex whose chromatin engagement is regulated by transcriptional activity and DNA damage signaling. The recipient will employ an integrative approach combining NMR spectroscopy, single-molecule biophysics, molecular dynamics simulations, and cellular assays to uncover how intrinsically disordered regions influence condensate properties and direct transitions between transcription, RNA maturation, and DNA repair.

Work is performed in San Antonio, Texas.

Abstract

Our laboratory investigates how intrinsically disordered proteins and intrinsically disordered regions (idrs) regulate nuclear processes essential for genome stability including transcription, RNA processing, and the DNA damage response (DDR). These functions are often coordinated through the formation of biomolecular condensates, dynamic, membraneless compartments that integrate CO-transcriptional activities. While idrs are known to drive condensate formation through multivalent interactions, the molecular principles by which other sequence-encoded features determine condensate material properties, and how these influence nuclear organization remain poorly defined. To address this knowledge GAP, over the next five years, we plan to identify the sequence and structural features that influence condensate mechanics, elucidate how IDR-facilitated interactions regulate factor recruitment and release, and develop advanced NMR strategies for characterizing large, disordered protein complexes in near- native contexts. We focus on two complementary systems: the RNA-binding protein EWS and its fusion variant EWS::FLI1, which perturbs condensate dynamics and transcriptional regulation; and the BRCA1-BARD1 heterodimer, a multifunctional DNA repair complex whose chromatin engagement is regulated by transcriptional activity and DNA damage signaling. Using an integrative approach combining NMR spectroscopy, single- molecule biophysics, molecular dynamics simulations, and cellular assays, we will uncover how idrs influence condensate properties, modulate folded domain behavior, and direct transitions between transcription, RNA maturation, and DNA repair. Our long-term vision is to define how IDR features such as local conformational preferences and specific interactions motifs contribute to the molecular grammar by which condensates encode regulatory function. This research will illuminate how dysregulation of phase behavior contributes to transcriptional stress and DDR impairment. By integrating structural biology, genome maintenance, and condensate biophysics, this research will advance fundamental understanding of nuclear organization and establish a foundation for targeting aberrant phase behavior in cancer, neurodegeneration and other human diseases.