Gain-of-function suppressors restore microtubule dynamics and rescue dominant-negative tubulinopathies.

Intergenic suppressors in tubulin genes restore microtubule dynamics and rescue dominant-negative tubulinopathies, with over 70% outperforming wild-type tubulin in human cells.

• Why it matters: Dominant-negative mutations in tubulin genes cause developmental disorders called tubulinopathies, and current treatments are limited. Understanding suppression mechanisms could lead to targeted therapies.
• What they did: Researchers performed suppressor screens in Caenorhabditis elegans, identifying three classes of missense suppressors that counteract mutant tubulins through distinct mechanisms, including assembly modulation and competitive exclusion. They validated these mechanisms in human cells and murine oocytes, demonstrating rescue of microtubule defects with selected suppressors. A detailed mutational analysis of TUBA1A revealed a landscape of gain-of-function suppressors supported by molecular simulations that restored protofilament geometry.
• The result: These findings establish a structural and functional framework for tubulin suppression, positioning intergenic suppressors as promising candidates for precision therapies targeting dominant tubulinopathies.