{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nYTHDC2 is a multidomain RNA helicase and m6A “reader” protein that integrates a conserved YTH domain—featuring an aromatic m6A‐binding pocket similar to other YTH proteins—with additional RNA-binding modules. Structural studies reveal that, like its relatives, YTHDC2 directly recognizes m6A-modified transcripts while coupling this recognition with ATP-dependent helicase activity, thereby influencing RNA fate and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n \nIn translational control, YTHDC2 plays multifaceted roles. In colon tumor cells it promotes metastasis by facilitating translation initiation of pro-metastatic mRNAs such as HIF-1α via unwinding of structured 5′ untranslated regions, while in hepatitis C virus (HCV) infection it interacts with an m6A-methylated nucleotide within the internal ribosome entry site (IRES) to support viral translation in a helicase-dependent manner. Similarly, during Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, YTHDC2 is recruited to m6A-modified IL-6 mRNA, enabling its escape from viral endonuclease cleavage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n\nIn various cancer settings, YTHDC2 exhibits context-dependent functions. In some tumors—such as esophageal squamous-cell carcinoma, rectal and papillary thyroid cancers—YTHDC2 expression is associated with suppression of cell proliferation and enhanced cell death through destabilization of oncogenic transcripts (for example, by indirectly downregulating factors like HOXA13 to inhibit system XC– activity and trigger ferroptosis, or via CYLD-mediated inactivation of the Akt pathway). Conversely, in prostate cancer and certain hepatocellular carcinoma models, increased YTHDC2 levels correlate with oncogenic properties, promoting growth, migration, and invasion. Moreover, prognostic studies link genetic variants and copy number alterations in YTHDC2 to patient outcomes in liver and lung cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n \nBeyond its role in regulating mRNA translation and stability in cancer and viral infections, YTHDC2 also influences cell differentiation and developmental processes. In human embryonic stem cells, it binds m6A-modified transcripts of transposable elements to recruit demethylases such as TET1 and thereby modulate epigenetic states that influence cell fate. Moreover, studies in mesenchymal stem cells indicate that YTHDC2 can regulate the balance between osteogenic and adipogenic differentiation. In the reproductive arena, functional integrity of YTHDC2 is critical; pathogenic variants have been linked to defects in meiosis leading to primary ovarian insufficiency and to azoospermia in men, underscoring its essential role in fertility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "19"}]}, {"type": "t", "text": "\n\nFinally, emerging evidence also implicates YTHDC2 in the cellular response to DNA damage. In the context of ultraviolet B (UVB)-induced skin injury, inhibition of YTHDC2 enhances DNA repair capacity, and its upregulation in cutaneous squamous cell carcinomas suggests a potential tumor-promoting role via m6A-dependent regulation of repair-related pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n\nCollectively, these findings demonstrate that YTHDC2 is a versatile regulator of RNA metabolism that couples m6A recognition with helicase activity to modulate mRNA stability, translation, and cellular signaling in diverse biological contexts ranging from viral infections and cancer to stem cell differentiation and reproductive biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chao Xu, Ke Liu, Hazem Ahmed, et al. 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