%0 Journal Article
%A Hänle-Kreidler, Simon
%A Richter, Kai
%A Hoffmann, Ingrid
%T The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of Histone 3 Lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage.
%J The journal of biological chemistry
%V 298
%N 12
%@ 0021-9258
%C Bethesda, Md.
%I Soc.
%M DKFZ-2022-02850
%P 102703
%D 2022
%Z ISSN 0021-9258 / #EA:F045#LA:F045#
%X During prolonged mitotic arrest induced by anti-microtubule drugs, cell fate decision is determined by two alternative pathways, one leading to cell death, the other inducing premature escape from mitosis by mitotic slippage. FBWX7, a member of the F-box family of proteins and substrate-targeting subunit of the SCF (SKP1-CUL1-F-Box) E3 ubiquitin ligase complex promotes mitotic cell death and prevents mitotic slippage, but molecular details underlying these roles for FBWX7 are unclear. In this study, we report that WDR5, a component of the mixed lineage leukemia (MLL) complex of Histone 3 Lysine 4 (H3K4) methyltransferases, is a substrate of FBXW7. We determined by co-immunoprecipitation experiments and in vitro binding assays that WDR5 interacts with FBXW7 in vivo and in vitro. SCF-FBXW7 mediates ubiquitination of WDR5 and targets it for proteasomal degradation. Furthermore, we find that WDR5 depletion counteracts FBXW7 loss-of-function by reducing mitotic slippage and polyploidization. In conclusion, our data elucidate a new mechanism in mitotic cell fate regulation which might contribute to prevent chemotherapy resistance in patients after anti-microtubule drug treatment.
%K FBXW7 (Other)
%K WDR5 (Other)
%K chemoresistance (Other)
%K mitotic slippage (Other)
%K ubiquitylation (ubiquitination) (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36395886
%R 10.1016/j.jbc.2022.102703
%U https://inrepo02.dkfz.de/record/182682