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Originally published In Press as doi:10.1074/jbc.M110271200 on December 18, 2001

J. Biol. Chem., Vol. 277, Issue 10, 8716-8723, March 8, 2002
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A Human DNA Helicase Homologous to the DNA Cross-link Sensitivity Protein Mus308*

Federica Marini and Richard D. WoodDagger

From the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15261

Repair of DNA interstrand cross-links is a challenging problem for cells. Many human gene products influence sensitivity to DNA cross-linking agents, but the mechanisms of cross-link repair are unknown. In Drosophila melanogaster, the mus308 mutation leads to marked sensitivity to DNA cross-linking agents. The C-terminal portion of the Mus308 polypeptide encodes a DNA polymerase, whereas a putative DNA helicase is encoded by the N-terminal portion. As a step toward isolating proteins involved in DNA cross-link repair, we searched for mammalian genes similar to the DNA helicase portion of Mus308. Human and mouse homologs were isolated from cDNA expression libraries and designated HEL308. Human HEL308 is on chromosome 4q21 and encodes a polypeptide of 1101 amino acids. The protein was expressed in insect cells and purified. HEL308 is a single-stranded DNA-dependent ATPase and DNA helicase. Mutation of a highly conserved lysine to methionine in helicase domain I eliminated both activities. The protein readily displaces 20- to 40-mer duplex oligonucleotides. Displacement of longer substrates was less efficient but was stimulated by the single-stranded DNA-binding protein RPA. Activity was supported by ATP or dATP but not other nucleotide triphosphates. The enzyme translocates on DNA with 3' to 5' polarity and behaves as a multimer upon gel filtration.

* This work was supported by postdoctoral fellowships from the European Molecular Biology and from Telethon (to F. M.), by the Imperial Cancer Research Fund, and by the University of Pittsburgh Cancer Institute.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF436845 and AF436846.

Dagger To whom correspondence should be addressed: S867 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel: 412-648-9248; Fax: 412-383-9822; E-mail: rdwood@pitt.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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