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• W4385574875 abstract "Abstract Menin is a protein that is regulated via protein-protein interactions by different binding partners, such as mixed lineage leukemia protein (MLL) and androgen receptor (AR). We observed that menin-AR and menin-MLL interactions are regulated by concentration-dependent dimerization of menin, and its interaction with cancer-related AR. As a result of its oligomerization-dependent interaction with both AR and MLL, menin is recruited into AR-RNA and MLL-RNA condensates formed by liquid-liquid phase separation (LLPS), with different outcomes under AR-overexpression or MLL-overexpression conditions representing different cancer types. At high concentrations promoting menin dimerization, it inhibits MLL-RNA LLPS, while making AR-RNA condensates less dynamic, i.e., more gel-like. Regions of AR show both negative/positive cooperativity in menin binding. AR contains a specific menin-binding region (MBR) in its intrinsically disordered N-terminal domain (NTD), menin binding of which is inhibited by the adjacent DNA-binding domain (DBD), but facilitated by a hinge region located between its DBD and ligand-binding domain (LBD) as well as by N terminus of AR. Interestingly, the hinge region reduces the propensity of full-length AR to undergo LLPS in the presence of RNA, which is facilitated by an alternative hinge region present in the tumor-specific AR isoform, AR-v7. As both menin and MLL are recruited into AR-driven, functional cellular condensates aggravated in the case of AR-v7, we posit that the menin-AR-MLL system represents a fine-tuned condensate module of transcription regulation that is balanced toward the tumor-suppressor activity of menin. Our results suggest that this balance can be upset by prevalent oncogenic events, such as menin upregulation and/or AR-v7 overexpression, in cancer." @default.
• W4385574875 created "2023-08-05" @default.
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• W4385574875 date "2023-08-04" @default.
• W4385574875 modified "2023-10-06" @default.
• W4385574875 title "Menin regulates androgen receptor- and MLL-driven condensation, upsetting regulation of cellular AR-driven transcription" @default.
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• W4385574875 doi "https://doi.org/10.1101/2023.08.04.551977" @default.
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