Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations.

ABSTRACT: Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function^1,2. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma³, the most common embryonal brain tumour in children⁴. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST⁵. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitution

SUBMITTER: Xie X 

PROVIDER: S-EPMC11882451 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature