Werner syndrome helicase

WRN is a member of the RecQ Helicase family. It is the only RecQ Helicase that contains 3' to 5' exonuclease activity. WRN is an oligomer that can act as a monomer when unwinding DNA, but as a dimer in solution or a tetramer when complexed with DNA, and has also been observed in hexameric forms. The diffusion of WRN has been measured to 1.62 \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} in nucleoplasm and 0.12 \textstyle \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} at nucleoli. Orthologs of WRN have been found in a number of other organisms, including Drosophila, Xenopus, and C. elegans. The amino terminus of WRN is involved in both helicase and nuclease activities, while the carboxyl-terminus interacts with p53, an important tumor suppressor. mRNA that codes for WRN has been identified in most human tissues. Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair. == Function ==

The exonuclease activities of WRN include degradation of recessed 3' ends and initiation of DNA degradation from a gap in dsDNA. WRN is important in repair of double strand breaks by homologous recombination or non-homologous end joining, repair of single nucleotide damages by base excision repair, and is effective in replication arrest recovery. WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences. WRN may function as an exonuclease in DNA repair, recombination, or replication, as well as resolution of DNA secondary structures. It is involved in branch migration at Holliday junctions, and it interacts with other DNA replication intermediates. Homologous recombinational repair WRN is active in homologous recombination. Cells defective in the WRN gene have a 23-fold reduction in spontaneous mitotic recombination, with especial deficiency in conversion-type events. WRN defective cells, when exposed to x-rays, have more chromosome breaks and micronuclei than cells with wild-type WRN. Cells defective in the WRN gene are not more sensitive than wild-type cells to gamma-irradiation, UV light, 4 – 6 cyclobutane pyrimidines, or mitomycin C, but are sensitive to type I and type II topoisomerase inhibitors. These findings suggested that the WRN protein takes part in homologous recombinational repair and in the processing of stalled replication forks. Non-homologous end joining WRN has an important role in non-homologous end joining (NHEJ) DNA repair. As shown by Shamanna et al., NEIL1 recognizes (targets) and removes certain ROS-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol. WRN also participates in BER through its interaction with Polλ. As shown by Pichierri et al.,) The interaction of WRN with the 9.1.1 complex results in prevention of DSB formation at stalled replication forks. Increased cellular WRN levels elicit increased cellular p53 levels and also potentiate p53-mediated apoptosis. Both repair of DNA damage and apoptosis are enzymatic processes necessary for maintaining integrity of the genome in humans. Cells with insufficient DNA repair tend to accumulate DNA damages, and when such cells are also defective in apoptosis they tend to survive even though excessive DNA damages are present. Replication of DNA in such deficient cells tends to lead to mutations and such mutations may cause cancer. Thus Werner syndrome helicase appears to have two roles related to the prevention of cancer, where the first role is to promote repair of specific types of damage and the second role is to induce apoptosis if the level of such DNA damage is beyond the cell's repair capability == Clinical significance ==

Werner syndrome Werner syndrome is caused by mutations in the WRN gene. This shortened protein may also be broken down too quickly, leading to a loss of Werner protein in the cell. Without normal Werner protein in the nucleus, cells cannot perform the tasks of DNA replication, repair, and transcription. Researchers are still determining how these mutations cause the appearance of premature aging seen in Werner syndrome. Cancer Microsatellite instability Recently, WRN has been identified as a synthetic lethality target in cancers containing a high number of microsatellites. These microsatellite-high (MSI-H) cancers have defects in their mismatch repair machinery (dMMR), which leads to the expansion of (TA)n dinucleotide repeats in the genome. These expanded (TA) dinucleotide microsatellites lead to the formation of secondary DNA structures (e.g. G-quadruplex) and rely on WRN to repair these bulky lesions. Because of this therapeutic hypothesis, inhibition of WRN has become an area of high interest for targeted therapies of MSI-H cancers, especially those that do not respond to immune checkpoint inhibition or chemotherapy. Deficiencies Cells expressing limiting amounts of WRN have elevated mutation frequencies compared with wildtype cells. Increased mutation may give rise to cancer. Patients with Werner Syndrome, with homozygous mutations in the WRN gene, have an increased incidence of cancers, including soft tissue sarcomas, osteosarcoma, thyroid cancer and melanoma. Mutations in WRN are rare in the general population. The rate of heterozygous loss-of-function mutation in WRN is approximately one per million. In a Japanese population the rate is 6 per 1,000, which is higher, but still infrequent. Mutational defects in the WRN gene are relatively rare in cancer cells compared to the frequency of epigenetic alterations in WRN that reduce WRN expression and could contribute to carcinogenesis. The situation is similar to other DNA repair genes whose expression is reduced in cancers due to mainly epigenetic alterations rather than mutations (see Frequencies of epimutations in DNA repair genes). The table shows results of analysis of 630 human primary tumors for WRN CpG island hypermethylation. This hypermethylation caused reduced protein expression of WRN, a common event in tumorigenesis. == Interactions ==

Werner syndrome ATP-dependent helicase has been shown to interact with: • BLM • DNA-PKcs, • FEN1, • Ku70, • Ku80, • PCNA, • TERF2, • WRNIP1, • RNF4, and • PIAS4. == Inhibitors ==