{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWDR77 (also known as MEP50 or p44) is an essential WD40-repeat protein that forms a stoichiometric complex with protein arginine methyltransferase 5 (PRMT5). This assembly constitutes the core of the methylosome, where WDR77 serves as a critical adaptor that mediates substrate recruitment and properly orients the targeted arginine residues on histones and other substrates for symmetric dimethylation. Structural studies, including both crystallographic and cryo‐electron microscopy analyses, have revealed that WDR77 intimately associates with the N‑terminal domain of PRMT5 in an octameric assembly, thereby guiding substrate recognition and modulating enzymatic activity. In addition, the PRMT5–WDR77 complex plays a central role in modifying key proteins—such as histones H3 and H4, and spliceosomal Sm proteins—to impact transcription, alternative splicing, and mRNA stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its structural role in the methylosome, WDR77 functions as a versatile cofactor for steroid hormone receptors—most notably the androgen and estrogen receptors. Acting as a transcriptional coactivator, WDR77 modulates the expression of hormone‐responsive genes, with its cellular impact profoundly influenced by its subcellular localization. Nuclear localization of WDR77 is associated with transcriptional activation and, depending on the tissue context, can either suppress or promote cell proliferation, as observed in prostate, ovarian, and breast cancers. Moreover, its dynamic distribution between the nucleus and the cytoplasm ties into its ability to orchestrate the appropriate balance between cell differentiation and growth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWDR77 is also a key player in oncogenesis and cellular growth regulation through its integration into multiple signaling networks. It has been implicated in the control of alternative splicing by partnering with factors such as ZNF326, and in the translational regulation of cell‐cycle regulators like E2F1/E2F3 via interactions with PDCD4 and eIF4A1. WDR77 further interacts with diverse proteins—including TSC22D2, SUZ12, and cGMP‑dependent protein kinase—to orchestrate gene repression or activation depending on the cellular context. Its activity is modulated by post‐translational modifications; for instance, deacetylation by SIRT7 attenuates the WDR77–PRMT5 interaction and the downstream histone modifications that drive transcriptional silencing. Moreover, the disruption of WDR77 expression or its mutation (as observed in familial papillary thyroid cancer) has been linked to enhanced cell proliferation and tumor progression, while agents such as curcumin can target its expression to suppress oncogenic signaling. These multifaceted roles underscore WDR77’s pivotal contribution to cell cycle control, gene regulation, and cancer development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephen Antonysamy, Zahid Bonday, Robert M Campbell, et al. 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