{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRRM1 is the regulatory subunit of ribonucleotide reductase, a key enzyme responsible for de novo synthesis of deoxyribonucleotides that are essential for DNA replication and repair. Many studies have demonstrated that overexpression of RRM1 in tumor tissues is associated with resistance to gemcitabine and other nucleoside analogs in cancers such as non–small‐cell lung cancer, pancreatic adenocarcinoma, biliary tract carcinoma, and even breast cancer. In these settings, low intratumoral RRM1 levels are commonly correlated with improved response rates, prolonged time to progression, and enhanced overall survival, making RRM1 a valuable predictive biomarker for tailoring chemotherapy regimens and overcoming drug resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role as a predictive biomarker for chemotherapeutic response, RRM1 is actively involved in the maintenance of genome integrity. It is rapidly recruited to sites of DNA damage in a Tip60‐dependent manner, thereby locally supplying deoxyribonucleotides required for efficient repair. Structural studies have revealed that RRM1 undergoes conformational changes upon binding various allosteric effectors (such as ATP, dATP, and TTP), which modulate not only its enzymatic activity but also its oligomeric state. Moreover, RRM1 forms functional complexes with partner subunits like RRM2 and p53R2, as demonstrated by in vitro reconstitution experiments, underscoring its central role in the regulation of ribonucleotide reductase holoenzyme activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent investigations have further expanded the functional repertoire of RRM1, revealing its involvement in modulating tumor behavior beyond nucleoside metabolism. Notably, overexpression of RRM1 has been linked to the induction of tumor suppressor factors such as PTEN, resulting in reduced phosphorylation of key signaling molecules and suppression of metastasis. In parallel, deregulation of RRM1 by microRNA networks has been shown to contribute to gemcitabine resistance, with targeted knockdown reversing resistance in preclinical models. These findings highlight RRM1’s promise not only as a marker to predict therapeutic response but also as a potential target for combination strategies aimed at enhancing chemosensitivity and limiting tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rafael Rosell, Giorgio Scagliotti, Kathleen D Danenberg, et al. 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