Spectrin: Its Role in DNA Repair

Studies in our laboratory demonstrate a role for nonerythroid α spectrin (αSpII∑*) in human cell nuclei as well as a new function for it in the cell, an involvement in DNA repair, in particular, repair of DNA interstrand cross‐links. In cells treated with a DNA interstrand cross‐linking agent, αSpII∑* co‐localizes in damage‐induced nuclear foci with XPF, a protein involved in cross‐link repair. It also co‐immunoprecipitates with XPF. HeLa cell nuclear αSpII∑* and purified bovine brain spectrin bind to DNA containing interstrand cross‐links. Also, anti‐αSpII∑* decreases levels of incisions produced by normal repair proteins on cross‐linked DNA. In cells from patients with Fanconi anemia (FA), a genetic disorder characterized by bone marrow failure, a predisposition to cancer and a defect in ability to repair DNA interstrand cross‐links, we have shown that there is a deficiency in αSpII∑*. This deficiency correlates with the repair defect in these cells. In FA, complementation group A cells, there is a loss of formation of XPF nuclear foci after cross‐link damage which correlates with a deficiency in αSpII∑* in these cells. siRNA‐mediated silencing of αII spectrin gene expression in normal human cells results in reduction of αII spectrin in these cells, decreased formation of damage‐induced nuclear foci and decreased cell survival after treatment with a cross‐linking agent. Based on these studies, we have proposed a model in which αSpII∑* is needed in DNA repair where it acts as a scaffold in the recruitment and alignment of repair proteins at sites of DNA damage. In FA cells, where there is a deficiency in αSpII∑*, this recruitment and repair are defective. Supported by NIH Grants R01 HL054860 and R01 ES011298.