Chapter category: Aging

Biochemical Characterization of the Werner Syndrome DNA Helicase—Exonuclease

This chapter appears in the following book:

Molecular Mechanisms of Werner's Syndrome

Edited by: Michel Lebel
ISBN: 0-306-48233-9
» Get more information about this book at landesbioscience.com «

Chapter authors:
Michael Fry

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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.

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Chapter category: Aging

Biochemical Characterization of the Werner Syndrome DNA Helicase—Exonuclease

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