Recombinant Human Bifunctional 3′-5′ exonuclease/ATP-dependent helicase WRN (WRN), partial

Function

Multifunctional enzyme that has magnesium and ATP-dependent 3'-5' DNA-helicase activity on partially duplex substrates (PubMed:9224595, PubMed:9288107, PubMed:9611231). Also has 3'->5' exonuclease activity towards double-stranded (ds)DNA with a 5'-overhang (PubMed:11863428). Has no nuclease activity towards single-stranded (ss)DNA or blunt-ended dsDNA (PubMed:11863428). Helicase activity is most efficient with (d)ATP, but (d)CTP will substitute with reduced efficiency; strand displacement is enhanced by single-strand binding-protein (heterotrimeric replication protein A complex, RPA1, RPA2, RPA3) (PubMed:9611231). Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity). Plays a role in double-strand break repair after gamma-irradiation (PubMed:9224595, PubMed:9288107, PubMed:9611231). Unwinds some G-quadruplex DNA (d(CGG)n tracts); unwinding seems to occur in both 5'-3' and 3'-5' direction and requires a short single-stranded tail (PubMed:10212265). d(CGG)n tracts have a propensity to assemble into tetraplex structures; other G-rich substrates from a telomeric or IgG switch sequence are not unwound (PubMed:10212265). Depletion leads to chromosomal breaks and genome instability (PubMed:33199508)

Subcellular Location

Nucleus, nucleolus; Nucleus; Nucleus, nucleoplasm; Chromosome

Disease Association

Werner syndrome (WRN) : A rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. [The disease is caused by variants affecting the gene represented in this entry] | Colorectal cancer (CRC) : A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. [The disease may be caused by variants affecting the gene represented in this entry]

Subunit

Monomer, and homooligomer (PubMed:11863428, PubMed:18596042, PubMed:20159463). May exist as homodimer, homotrimer, homotetramer and/or homohexamer (PubMed:11863428, PubMed:18596042, PubMed:20159463). Homotetramer, or homohexamer, when bound to DNA (PubMed:11863428, PubMed:18596042, PubMed:20159463). Interacts via its N-terminal domain with WRNIP1 (By similarity). Interacts with EXO1, PCNA and SUPV3L1 (PubMed:12704184, PubMed:17961633). Interacts with PML (isoform PML-4) (PubMed:21639834). Interacts (via KBM motif) with XRCC5 and XRCC6; promoting recruitment to DNA damage sites (PubMed:27063109). Interacts with RECQL5; this interaction stimulates WRN helicase activity on DNA fork duplexes (PubMed:23180761)

• Yu C.-E. et al. Positional cloning of the Werner's syndrome gene. — Science (1996)
• Agrelo R. et al. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. — Proc. Natl. Acad. Sci. U.S.A. (2006)
• Paeper B.W. et al. Genomic structure of the human Werner's gene and cloning of the mouse homolog. (AUG-)
• PubMed: CI-9GALKN8DBTP2G (OCT-)
• Nusbaum C. et al. DNA sequence and analysis of human chromosome 8. — Nature (2006)
• Gray M.D. et al. The Werner syndrome protein is a DNA helicase. — Nat. Genet. (1997)
• Suzuki N. et al. DNA helicase activity in Werner's syndrome gene product synthesized in a baculovirus system. — Nucleic Acids Res. (1997)
• Shen J.C. et al. Characterization of Werner syndrome protein DNA helicase activity: directionality, substrate dependence and stimulation by replication protein A. — Nucleic Acids Res. (1998)