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.
Nucleic Acids Research (Impact Factor: 9.11). 02/2006; 34(22):6673-83. DOI: 10.1093/nar/gkl964
Source: PubMed


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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Available from: Sudha Sharma
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    • "It will be of interest to determine if any of the Fe–S cluster helicases behave in a cooperative manner, and if the redox activity of the Fe–S cluster plays a role in this capacity. In this regard, previously we showed that inhibition of FANCJ helicase activity by a polyglycol linkage that disrupts the sugar phosphate backbone can be overcome by an increased length in the 5′ single-stranded DNA loading tail (70). This suggested a model in which a leading FANCJ helicase molecule is pushed forward by other FANCJ helicase molecules loaded behind it to complete unwinding. "
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