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| Home > Publications database > The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of Histone 3 Lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage. |
| Home > Publications database > The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of Histone 3 Lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage. |
| Journal Article | DKFZ-2022-02850 |
; ;
2022
Soc.
Bethesda, Md.
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Please use a persistent id in citations: doi:10.1016/j.jbc.2022.102703
Abstract: 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.
Keyword(s): FBXW7 ; WDR5 ; chemoresistance ; mitotic slippage ; ubiquitylation (ubiquitination)
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