TY  - JOUR
AU  - Hänle-Kreidler, Simon
AU  - Richter, Kai
AU  - Hoffmann, Ingrid
TI  - The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of Histone 3 Lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage.
JO  - The journal of biological chemistry
VL  - 298
IS  - 12
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.
M1  - DKFZ-2022-02850
SP  - 102703
PY  - 2022
N1  - ISSN 0021-9258 / #EA:F045#LA:F045#
AB  - 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.
KW  - FBXW7 (Other)
KW  - WDR5 (Other)
KW  - chemoresistance (Other)
KW  - mitotic slippage (Other)
KW  - ubiquitylation (ubiquitination) (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36395886
DO  - DOI:10.1016/j.jbc.2022.102703
UR  - https://inrepo02.dkfz.de/record/182682
ER  -