Sommers Joshua A, Rawtani Nina, Gupta Rigu, Bugreev Dmitry V, Mazin Alexander V, Cantor Sharon B, Brosh Robert M
Laboratory of Molecular Gerontology, NIA, National Institutes of Health, National Institutes of Health Biomedical Research Center, Baltimore, Maryland 21224, USA.
J Biol Chem. 2009 Mar 20;284(12):7505-17. doi: 10.1074/jbc.M809019200. Epub 2009 Jan 16.
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.
FANCJ解旋酶的突变使个体易患乳腺癌，并且在基因上与范可尼贫血（FA）互补组J相关联。FA是一种染色体不稳定疾病，其特征为多种先天性异常、进行性骨髓衰竭和高癌症风险。有人提出FANCJ在FANCD2单泛素化的下游发挥作用，这是FA途径中的一个关键事件。有证据支持FANCJ在双链断裂修复的同源重组途径中发挥作用。为了了解FANCJ的分子功能，我们研究了纯化的FANCJ重组蛋白除了解开传统双链DNA底物外，利用其马达ATP酶功能进行其他活动的能力。这些研究工作导致发现FANCJ ATP水解可用于使蛋白质-DNA复合物不稳定并解开三螺旋交替DNA结构。FANCJ的这些新催化功能可能对其在细胞DNA修复、重组或解决复制过程中的DNA结构障碍方面的作用很重要。与此一致的是，我们表明FANCJ可以抑制RAD51链交换，这种活性可能对其通过同源重组控制DNA修复的作用很重要。
