{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTelomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, a ribonucleoprotein enzyme essential for adding telomeric repeats to the ends of chromosomes, thereby maintaining telomere length and genomic stability. In normal human cells, TERT expression is tightly regulated so that telomere shortening eventually leads to replicative senescence—a critical tumor‐suppressive mechanism—but its controlled activity also supports the proliferation of stem cells and other renewing tissues. In this context, studies in primary fibroblasts and other cell systems have established that proper TERT activity is required not only for telomere elongation but also for an optimal DNA damage response and cell‐cycle regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn many human cancers, however, genetic alterations—most notably in the promoter region of the TERT gene—disrupt its normal regulation and lead to aberrant reactivation of telomerase. These somatic promoter mutations (which create de novo binding motifs for ETS transcription factors) and structural rearrangements have been detected across a wide spectrum of malignancies including melanoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", lung cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", glioma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", thyroid carcinoma"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": ", hepatocellular carcinoma"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": ", urothelial carcinoma"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "25"}]}, {"type": "t", "text": ", neuroblastoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": ", as well as pancreatic"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": ", breast"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "32"}]}, {"type": "t", "text": "and testicular germ cell tumors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": " Such alterations lead to marked upregulation of TERT transcription and telomerase activity, thereby enabling cancer cells to overcome normal replicative limits and contributing to tumor aggressiveness and poor clinical outcomes.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical function in telomere elongation, emerging evidence indicates that TERT can also exert “non‐canonical” activities. These include participation in mitochondrial processes and the DNA damage response as well as engagement in an RNA‐dependent RNA polymerase complex with the mitochondrial RNA processing endoribonuclease (RMRP), which may contribute to the regulation of gene expression through the production of small interfering RNAs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Such functions underscore a broader role for TERT in cell physiology that extends beyond telomere maintenance.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe clinical implications of TERT deregulation are profound. 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