{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ERCC1 is a critical component of the ERCC1/XPF structure‐specific endonuclease complex that plays a central role in nucleotide excision repair (NER) by mediating the 5′ incision at helix‐distorting DNA lesions induced by ultraviolet light and platinum‐based agents."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition to its canonical function in NER, ERCC1/XPF is essential for processing DNA interstrand crosslinks and facilitating the repair of double‐strand breaks that arise during DNA replication, thereby contributing to genomic stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Its activity also extends to telomere homeostasis; for example, following inhibition of the shelterin protein TRF2, ERCC1/XPF removes the 3′ telomeric overhang to allow proper chromosomal end‐processing and to prevent aberrant nonhomologous end joining."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the clinical context, levels of ERCC1 expression and specific genetic polymorphisms (such as the synonymous codon 118 C/T change) have been widely investigated as predictive biomarkers for response to platinum‐based chemotherapy in several malignancies including non–small‐cell lung cancer, colorectal cancer, and bladder cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Generally, lower ERCC1 levels correlate with increased drug sensitivity and improved clinical outcomes, whereas higher ERCC1 expression is associated with enhanced DNA repair capacity and chemoresistance; indeed, experimental models of acquired resistance have demonstrated that up‐regulation of ERCC1 can contribute to diminished platinum sensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, rare inherited ERCC1 deficiencies or deleterious mutations have been linked to severe developmental and multisystem disorders, highlighting its indispensable role in DNA repair and genomic integrity in humans."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laura J Niedernhofer, Hanny Odijk, Magda Budzowska, et al. 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