A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.

A conserved regulatory helix in HUWE1 controls ASCL1 degradation via its phospho-degron in small cell lung cancer, revealing a new autoinhibitory mechanism.

• Why it matters: Targeting lineage-defining transcription factors like ASCL1 is challenging due to their lack of ligandable pockets, limiting therapeutic options for small cell lung cancer.
• What they did: Using genome-wide CRISPR knockout and base editor tiling screens with an endogenous reporter, the study identified HUWE1 as the main regulator of ASCL1 stability and uncovered a regulatory helix within HUWE1.
• The result: Disrupting the regulatory helix accelerates degradation of ASCL1 and other substrates, but stabilizing ASCL1 impairs cancer cell proliferation, highlighting the importance of controlled proteasome turnover for transcription factor function.