Nucleic Acids Research Advance Access originally published online on December 1, 2006
Nucleic Acids Research 2006 34(22):6673-6683; doi:10.1093/nar/gkl964
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Nucleic Acids Research, 2006, Vol. 34, No. 22 6673-6683
© 2006 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 |
Inhibition of BACH1 (FANCJ) helicase by backbone discontinuity is overcome by increased motor ATPase or length of loading strand
Laboratory of Molecular Gerontology, National Institute on Aging NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA 1 Department of Cancer Biology, University of Massachusetts Medical School Lazare Research Building, Worcester, MA 01605, USA
*To whom correspondence should be addressed. Tel: +1 410 558 8578; Fax: +1 410 558 8157; Email: broshr{at}grc.nia.nih.gov
Received September 20, 2006. Revised October 23, 2006. Accepted October 25, 2006.
The BRCA1 associated C-terminal helicase (BACH1) associated with breast cancer has been implicated in double strand break (DSB) repair. More recently, BACH1 (FANCJ) has been genetically linked to the chromosomal instability disorder Fanconi Anemia (FA). Understanding the roles of BACH1 in cellular DNA metabolism and how BACH1 dysfunction leads to tumorigenesis requires a comprehensive investigation of its catalytic mechanism and molecular functions in DNA repair. In this study, we have determined that BACH1 helicase contacts with both the translocating and the non-translocating strands of the duplex are critical for its ability to track along the sugar phosphate backbone and unwind dsDNA. An increased motor ATPase of a BACH1 helicase domain variant (M299I) enabled the helicase to unwind the backbone-modified DNA substrate in a more proficient manner. Alternatively, increasing the length of the 5' tail of the DNA substrate allowed BACH1 to overcome the backbone discontinuity, suggesting that BACH1 loading mechanism is critical for its ability to unwind damaged DNA molecules.
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