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Nucleic Acids Research Advance Access originally published online on April 25, 2008
Nucleic Acids Research 2008 36(10):3366-3373; doi:10.1093/nar/gkn225
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Nucleic Acids Research, 2008, Vol. 36, No. 10 3366-3373
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Rapid unwinding of triplet repeat hairpins by Srs2 helicase of Saccharomyces cerevisiae

Alok Dhar1 and Robert S. Lahue1,2,*

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Box 986805, Omaha, NE 68198-6805, USA and 2Department of Biochemistry, National University of Ireland, Galway, Ireland

*To whom correspondence should be addressed. Tel: +353 91 495756; Fax: +353 91 495504; Email: bob.lahue{at}nuigalway.ie

Received March 12, 2008. Revised April 9, 2008. Accepted April 10, 2008.

Expansions of trinucleotide repeats cause at least 15 heritable human diseases. Single-stranded triplet repeat DNA in vitro forms stable hairpins in a sequence-dependent manner that correlates with expansion risk in vivo. Hairpins are therefore considered likely intermediates during the expansion process. Unwinding of a hairpin by a DNA helicase would help protect against expansions. Yeast Srs2, but not the RecQ homolog Sgs1, blocks expansions in vivo in a manner largely dependent on its helicase function. The current study tested the idea that Srs2 would be faster at unwinding DNA substrates with an extrahelical triplet repeat hairpin embedded in a duplex context. These substrates should mimic the relevant intermediate structure thought to occur in vivo. Srs2 was faster than Sgs1 at unwinding several substrates containing triplet repeat hairpins or another structured loop. In contrast, control substrates with an unstructured loop or a Watson–Crick duplex were unwound equally well by both enzymes. Results with a fluorescently labeled, three-way junction showed that Srs2 unwinding proceeds unabated through extrahelical triplet repeats. In summary, Srs2 maintains its facile unwinding of triplet repeat hairpins embedded within duplex DNA, supporting the genetic evidence that Srs2 is a key helicase in Saccharomyces cerevisiae for preventing expansions.


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