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Nucleic Acids Research Advance Access originally published online on November 26, 2007
Nucleic Acids Research 2008 36(2):393-403; doi:10.1093/nar/gkm1025
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Nucleic Acids Research, 2008, Vol. 36, No. 2 393-403
© 2007 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

The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities

Géraldine Farge1, Teresa Holmlund1, Julia Khvorostova1, Reza Rofougaran2, Anders Hofer2 and Maria Falkenberg1,*

1Division of Metabolic Diseases, Karolinska Institutet, Novum, SE-141 86 Stockholm and 2Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden

*To whom correspondence should be addressed. Tel: +46 8 58583730; Fax: +46 8 779 5383; Email: maria.falkenberg{at}ki.se

Received March 5, 2007. Revised October 4, 2007. Accepted October 29, 2007.

The TWINKLE protein is a hexameric DNA helicase required for replication of mitochondrial DNA. TWINKLE displays striking sequence similarity to the bacteriophage T7 gene 4 protein (gp4), which is a bi-functional primase-helicase required at the phage DNA replication fork. The N-terminal domain of human TWINKLE contains some of the characteristic sequence motifs found in the N-terminal primase domain of the T7 gp4, but other important motifs are missing. TWINKLE is not an active primase in vitro and the functional role of the N-terminal region has remained elusive. In this report, we demonstrate that the N-terminal part of TWINKLE is required for efficient binding to single-stranded DNA. Truncations of this region reduce DNA helicase activity and mitochondrial DNA replisome processivity. We also find that the gp4 and TWINKLE are functionally distinct. In contrast to the phage protein, TWINKLE binds to double-stranded DNA. Moreover, TWINKLE forms stable hexamers even in the absence of Mg2+ or NTPs, which suggests that an accessory protein, a helicase loader, is needed for loading of TWINKLE onto the circular mtDNA genome.


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