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First published online 15 January 2003
doi: 10.1242/jcs.00294

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Nonerythroid II spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links

Department of Pathology and Laboratory Medicine, UMDNJ — New Jersey Medical School and the Graduate School of Biomedical Sciences, Newark, NJ 07103, USA

* Author for correspondence (e-mail: mlambert{at}umdnj.edu)

Accepted 26 November 2002

The events responsible for repair of DNA interstrand cross-links in mammalian cells, the proteins involved and their interactions with each other are poorly understood. The present study demonstrates that the structural protein nonerythroid spectrin (SpII*), present in normal human cell nuclei, plays an important role in repair of DNA interstrand cross-links. These results show that SpII* relocalizes to nuclear foci after damage of normal human cells with the DNA interstrand cross-linking agent 8-methoxypsoralen plus ultraviolet A (UVA) light and that FANCA and the known DNA repair protein XPF localize to the same nuclear foci. That SpII* is essential for this re-localization is demonstrated by the finding that in cells from patients with Fanconi anemia complementation group A (FA-A), which have decreased ability to repair DNA interstrand cross-links and decreased levels of SpII*, there is a significant reduction in formation of damage-induced XPF as well as SpII* nuclear foci, even though levels of XPF are normal in these cells. In corrected FA-A cells, in which levels of SpII* are restored to normal, numbers of damage-induced nuclear foci are also returned to normal. Co-immunoprecipitation studies show that SpII*, FANCA and XPF co-immunoprecipitate with each other from normal human nuclear proteins. These results demonstrate that SpII*, FANCA and XPF interact with each other in the nucleus and indicate that there is a close functional relationship between these proteins. These studies suggest that an important role for SpII* in the nucleus is to act as a scaffold, aiding in recruitment and alignment of repair proteins at sites of damage.

Key words: Spectrin, FANCA, XPF, DNA interstrand cross-link, DNA repair

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