WRN (WRN RecQ like helicase; HGNC:12791, NCBI Gene ID 7486) is a human locus mapped to chromosome band 8p12 that encodes bifunctional ATP-dependent 3-prime->5-prime DNA helicase & 3-prime->5-prime exonuclease WRN (1,432 aa; 162 kDa; EC 3.6.4.12). WRN acts in resolution of G-quadruplexes at lagging-strand telomeres, stalled replication fork restart & homologous recombination, together with LMNA (Hutchinson-Gilford Progeria Gene), TERT (Telomerase Reverse Transcriptase Gene), and SIRT6 (Recruits WRN to Telomeric Chromatin). Encodes the bifunctional RecQ DNA helicase and exonuclease mutated in adult-onset Werner progeroid syndrome and required for survival of microsatellite-unstable tumors.
Resolution of G-quadruplexes at lagging-strand telomeres, stalled replication fork restart & homologous recombination
Clinical / Therapeutic Role
Biallelic LoF causes Werner syndrome (adult progeria); synthetic-lethal oncology target in MSI-H mismatch-repair-deficient cancers
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 35-exon gene spanning ~140 kb on chromosome 8p12, unique among the five human RecQ helicases (RECQL, BLM, WRN, RECQL4, RECQL5) in possessing both an N-terminal DnaQ-like 3-prime->5-prime exonuclease domain (residues 38–236) and a central ATP-dependent 3-prime->5-prime DEAH-box helicase domain followed by RQC and HRDC DNA-binding domains.
Cellular & Tissue Expression Profile: Expressed in the nucleolus of proliferating cells and rapidly relocalized to nuclear replication foci, telomeres, and DNA double-strand breaks upon phosphorylation by ATR or ATM and deacetylation by SIRT1 and SIRT6.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Unwinds non-canonical secondary DNA structures—including G-quadruplexes in the G-rich lagging-strand telomeric template, Holliday junctions, D-loops, and regressing chicken-foot replication forks—enabling smooth telomere replication alongside shelterin protein TRF2 and preventing telomere fragility and chromosomal fusions.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic truncating loss-of-function mutations eliminate the C-terminal nuclear localization signal and cause autosomal recessive Werner syndrome, the classic adult-onset segmental progeria characterized by normal childhood development until puberty followed by lack of the adolescent growth spurt, bilateral cataracts, premature hair graying/alopecia, scleroderma-like skin atrophy, type 2 diabetes, osteoporosis, premature atherosclerosis, and mesenchymal sarcomas.
Therapeutic & Clinical Pharmacology: Genome-wide CRISPR knockout screens discovered that microsatellite-instability-high (MSI-H / mismatch-repair-deficient) colorectal, endometrial, and gastric cancers undergo massive TA-dinucleotide repeat expansions that form cruciform DNA structures strictly requiring WRN helicase to unwind—making covalent and allosteric WRN helicase inhibitors (such as HRO761 and VVD-214) a premier synthetic-lethal precision oncology class.