Werner syndrome ATP-dependent helicase

Werner syndrome ATP-dependent helicase also known as DNA helicase, RecQ-like type 3 is an is_associated_with::enzyme that in humans is encoded by the WRN is_associated_with::gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded is_associated_with::DNA. These activities are necessary before DNA can be copied in preparation for cell division (is_associated_with::DNA replication). Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

The WRN gene is located on the short (p) arm of chromosome 8 between positions 12 and 11.2, from is_associated_with::base pair 31,010,319 to base pair 31,150,818.

Structure and function
WRN is a member of the RecQ Helicase family. It is the only RecQ Helicase that contains 3' to 5' is_associated_with::exonuclease activity. These exonuclease activities include degradation of recessed 3' ends and initiation of DNA degradation from a gap in dsDNA. WRN is important in reparation of double stranded breaks, nonhomologous end joining, and is_associated_with::base excision repair. WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.

WRN is an is_associated_with::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 tetrameric and 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 Drosohphila, is_associated_with::Xenopus, and C. elegans. WRN is important to genome stability, and cells with mutations to WRN are more susceptible to DNA damage and DNA breaks.

The amino terminus of WRN is involved in both is_associated_with::helicase and is_associated_with::nuclease activities, while the carboxyl-terminus interacts with is_associated_with::p53, an important tumor suppressor. 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 is_associated_with::Holliday junctions, and it interacts with other DNA replication intermediates. mRNA that codes for WRN has been identified in most human tissues.

Post-translational modification
Phosphorylation of WRN at serine/threonine inhibits helicase and exonuclease activities which are important to post-replication DNA repair. De-phosphorylation at these sites enhances the catalytic activities of WRN. Phosphorylation may affect other post-translational modifications, including sumoylation and acetylation.

Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.

Clinical significance
is_associated_with::Werner syndrome is caused by is_associated_with::mutations in the WRN gene. More than 20 mutations in the WRN gene are known to cause Werner syndrome. Many of these mutations result in an abnormally shortened Werner protein. Evidence suggests that the altered is_associated_with::protein is not transported into the is_associated_with::cell nucleus, where it normally interacts with DNA. 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 is_associated_with::aging seen in Werner syndrome.

Interactions
Werner syndrome ATP-dependent helicase has been shown to interact with:


 * BLM
 * is_associated_with::DNA-PKcs,
 * FEN1,
 * is_associated_with::Ku70,
 * is_associated_with::Ku80,
 * is_associated_with::P53,
 * is_associated_with::PCNA,
 * is_associated_with::TERF2, and
 * is_associated_with::WRNIP1.