Abstract
Mutations in the FANCJ helicase predispose individuals to breast cancer and are genetically linked to the Fanconi anemia (FA) complementation group J. FA is a chromosomal instability disorder characterized by multiple congenital anomalies, progressive bone marrow failure, and high cancer risk. FANCJ has been proposed to function downstream of FANCD2 monoubiquitination, a critical event in the FA pathway. Evidence supports a role for FANCJ in a homologous recombination pathway of double strand break repair. In an effort to understand the molecular functions of FANCJ, we have investigated the ability of purified FANCJ recombinant protein to use its motor ATPase function for activities in addition to unwinding of conventional duplex DNA substrates. These efforts have led to the discovery that FANCJ ATP hydrolysis can be used to destabilize protein-DNA complexes and unwind triple helix alternate DNA structures. These novel catalytic functions of FANCJ may be important for its role in cellular DNA repair, recombination, or resolving DNA structural obstacles to replication. Consistent with this, we show that FANCJ can inhibit RAD51 strand exchange, an activity that is likely to be important for its role in controlling DNA repair through homologous recombination.
Highlights
Mutations in the FANCJ helicase predispose individuals to breast cancer and are genetically linked to the Fanconi anemia (FA) complementation group J
Consistent with this, we show that FANCJ can inhibit RAD51 strand exchange, an activity that is likely to be important for its role in controlling DNA repair through homologous recombination
Increasing concentrations of FANCJ-wild type (WT) were incubated in the presence of ATP with a radiolabeled oligonucleotide that had streptavidin bound to the biotin conjugated either 28 or 52 nt from the 5Ј-end of the 66-mer oligonucleotide
Summary
Mutations in the FANCJ helicase predispose individuals to breast cancer and are genetically linked to the Fanconi anemia (FA) complementation group J. In an effort to understand the molecular functions of FANCJ, we have investigated the ability of purified FANCJ recombinant protein to use its motor ATPase function for activities in addition to unwinding of conventional duplex DNA substrates These efforts have led to the discovery that FANCJ ATP hydrolysis can be used to destabilize proteinDNA complexes and unwind triple helix alternate DNA structures. The DOG-1 protein in nematodes, which has sequence similarity to the FANCJ helicase domain, has been proposed to have a role in the resolution of G4 DNA structures based on the observation that dog-1 (deletions of guanine-rich DNA) mutations show germ line as well as somatic deletions in genes containing guanine-rich DNA [18] Another source of genomic instability and perturbation to cellular processes of nucleic acid metabolism is the DNA triple helix, an alternate DNA structure stabilized by Hoogsteen hydrogen bonding of the third strand to the DNA double helix that poses a source of genomic instability and perturbs cellular processes of nucleic acid metabolism [19, 20]. Triplex formation by the Friedreich ataxia (GAA)n repeat results in reduced expression of the frataxin gene [21], inhibits DNA replication in vitro [21, 22], and causes replication forks to stall at (GAA)n repeats in vivo [23]
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