{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPUF60 functions as a pivotal splicing factor that promotes correct and alternative pre‐mRNA splicing. It facilitates the recognition of weak 3′ splice‐sites in a manner functionally analogous to U2AF65 and binds to U‐rich sequences via its central RNA recognition motifs. Structural and biochemical studies have shown that PUF60 can engage with splice site sequences—often inducing conformational changes such as RNA looping—to modulate spliceosome assembly and exon inclusion. These properties underscore its central role in both constitutive and regulated splicing events."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its splicing activity, PUF60 (also known in its alternatively spliced isoform as FIR) plays an important role in transcriptional regulation. It interacts with regulatory DNA elements such as the far upstream element (FUSE) to modulate c‐myc transcription and cooperates with other factors to form dynamic complexes that fine‐tune gene expression. Furthermore, PUF60 influences critical cellular processes by regulating viral gene expression (e.g. hepatitis B virus transcripts), TERT promoter activity in renal cell carcinoma, and cell cycle effectors such as P27Kip1 through its associations with DNA damage response proteins. In these ways, PUF60 integrates transcriptional control with RNA processing to influence cell proliferation and oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, altered PUF60 dosage or splicing has been implicated in a spectrum of human disorders. Heterozygous variants and microdeletions affecting PUF60 are now recognized as a major contributor to developmental syndromes—including Verheij syndrome—characterized by craniofacial dysmorphism, cardiac, skeletal, renal, ocular, and neurodevelopmental anomalies. In addition, aberrant expression and the generation of autoantibodies against PUF60 have been documented in various cancers and systemic autoimmune conditions, highlighting its potential utility as both a diagnostic biomarker and a therapeutic target. 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