Chapter category: Aging
Biochemical Characterization of the Werner Syndrome DNA Helicase—Exonuclease
Molecular Mechanisms of Werner's Syndrome
Edited by: Michel LebelISBN: 0-306-48233-9
» Get more information about this book at landesbioscience.com «
Chapter authors:
Michael Fry
The positional cloning in 1996 of WRN, the human gene defective in Werner syndrome (WS), launched an explosive experimental activity that culminated in the expression, purification and comprehensive characterization of its product protein – the WRN DNA helicase-exonuclease. Being a member of the RecQ family of DNA helicases, WRN possesses a 3’g5’ helicase activity that resides in a 7-motif domain at the center of the 1432 amino acid polypeptide. In addition, WRN is distinguished from all the other RecQ-like helicases in that it also has a 3’g5’ exonuclease activity sited in a 3-motif N-terminal domain in the WRN protein. A distinctive feature of the helicase activity of WRN is its capacity to preferentially unwind alternate DNA structures that include tetra- and triple-helical DNA, duplex DNA containing a single-strand bubble, and 4-way X junction DNA. Correspondingly, the WRN 3’g5’ exonuclease is also distinguished by its proclivity to preferentially digest non-canonical DNA structures such as bubble-containing duplex DNA, extra-helical single-strand loops and 3- and 4-way X junctions. The penchant of both the helicase and exonuclease for alternative DNA structures might reflect their roles in resolving aberrant DNA formations that form during the metabolism of cellular DNA. Some data indicate that the WRN helicase and nuclease act in coordination. However, it is not clear yet how the two activities operate in concert despite their opposite directions of advancement along the processed DNA molecule. Data described elsewhere in this volume indicate that the association of WRN protein with various DNA metabolism proteins modulates the innate properties of its helicase and exonuclease activities. Conceivably, therefore, a better understanding of the modes of operation and in vivo roles of the WRN protein are to be gained by studying the properties of its helicase and exonuclease in reconstituted multiprotein complexes.
Additional chapters from this book:
Replicative Senescence, Telomeres and Werner’s Syndrome
Richard G.A. Faragher
Werner’s syndrome (WS) is studied as a model of accelerated aging and results from mutations in a recQ helicase (WRN). WS fibroblasts show a mutator phenotype (producing large DNA deletions), replic...
Proposed Biological Functions for the Werner Syndrome Protein in DNA Metabolism
Patricia L. Opresko, Jeanine A. Harrigan, Wen-Hsing Cheng, Robert M. Brosh, Jr. and Vilhelm A. Bohr
Werner syndrome is a premature aging disease that is characterized by genomic instability. The gene defective in Werner syndrome encodes a protein with helicase and exonuclease activities. This chap...
Proteins That Interact with the Werner Syndrome Gene Product
Dana Branzei and Takemi Enomoto
Werner syndrome is an autosomal recessive disorder characterized by premature onset of age-related diseases, increased cancer incidence, and genomic instability. Biochemical characterization has sho...
Clinical Aspects of Werner’s Syndrome: Its Natural History and the Genetics of the Disease
Makoto Goto
Werner’s syndrome, caused by a mutation in the WRN (or RecQ3) helicase gene, shows a variety of clinical and biochemical-aging phenotypes at an early stage of life followed by death at an average ag...
Yeast RecQ Helicases: Clues to DNA Repair, Genome Stability and Aging
Rozalyn M. Anderson and David A. Sinclair
The budding yeast Saccharomyces cerevisiae has been used as model for a wide range of cellular processes, including those related to the RecQ-associated progeroid disease, Werner’s syndrome (WS). In...
Biochemical Characterization of the Werner Syndrome DNA Helicase—Exonuclease
Michael Fry
The positional cloning in 1996 of WRN, the human gene defective in Werner syndrome (WS), launched an explosive experimental activity that culminated in the expression, purification and comprehensive c...
Biochemical Roles of RecQ Helicases
Payam Mohaghegh and Ian D. Hickson
The RecQ family of DNA helicases appears to influence DNA repair, replication and/or homologous recombination pathways. In humans, a defect in the RecQ family helicases encoded by the BLM, WRN a...
Sensitivity of Werner's Syndrome Cells to DNA Damaging Agents: Insights into the Biological Functions of the Werner Protein
Adayabalam S. Balajee and Fabrizio Palitti
Werner’s syndrome (WS) is a human autosomal recessive disorder characterized by many symptoms of accelerated aging. The gene responsible for Werner’s syndrome (WRN) has been cloned and the protein has...
Potential Function of the Werner's Syndrome Homologue in the African Clawed Frog and the Mouse
Michel Lebel and Philip Leder
After the discovery of the gene responsible for WS in the human, genes with high homology to WRN were found in the mouse Mus musculus and the African clawed frog Xenopus laevis genome. These lab...
