Spectrin: Its Role in DNA Repair

Abstract

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.