{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRRM2B encodes the p53‐inducible small subunit of ribonucleotide reductase (p53R2), a protein that is fundamental to deoxyribonucleotide triphosphate (dNTP) production for both nuclear DNA repair and mitochondrial DNA (mtDNA) synthesis. Mutations in RRM2B have been shown to cause severe mtDNA depletion syndromes and related disorders, as evidenced by cases of profound muscle mtDNA loss and early‐onset mitochondrial dysfunction. In quiescent or postmitotic cells, where the traditional S‐phase subunit R2 is absent, p53R2 is indispensable for maintaining mtDNA and enabling efficient repair of damaged nuclear DNA. Dysfunctional p53R2, whether by missense, nonsense, or splice‐site mutations, disrupts this dNTP supply, thereby impairing both mtDNA replication and genomic integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in nucleotide synthesis, RRM2B is tightly regulated in response to DNA damage and stress through both p53‐dependent and p53‐independent mechanisms. In numerous studies, altered expression of p53R2 has been linked to changes in cell cycle regulation, apoptotic sensitivity, and epithelial–mesenchymal transition in various cancers, including lung, cervical, head and neck, and prostate carcinomas. Its involvement in key signaling cascades—such as those mediated by Akt, MEK, or even transcription factors like E2F1 and FOXO3—underscores its dual capacity as both a guardian of genomic stability and a modulator of tumor progression. Changes in p53R2 levels have been shown to influence sensitivity to radiochemotherapy and genotoxic agents, making its expression a promising prognostic biomarker in oncology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence has further illuminated the complex regulation and multifunctional nature of RRM2B. Detailed structural and biochemical studies have revealed differences between p53R2 and the canonical R2 subunit, explaining distinct aspects of iron coordination, radical generation, and binding affinity to the R1 catalytic subunit. In addition, p53R2 exerts nontraditional roles by directly interacting with metabolic enzymes such as mitochondrial thioredoxin reductase (TrxR2) and pyrroline‐5‐carboxylate reductases, thereby contributing to reactive oxygen species (ROS) scavenging and mitochondrial homeostasis. Furthermore, its expression can be modulated through alternative pathways—including p53-independent routes mediated by factors like E2F1—which may ultimately impact apoptotic thresholds and the cellular response to genotoxic as well as mechanical stress. Collectively, these insights underscore the pivotal role of RRM2B in safeguarding both nuclear and mitochondrial genomes and suggest that targeting its regulatory networks could provide novel therapeutic opportunities."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "49"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alice Bourdon, Limor Minai, Valérie Serre, et al. 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