Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage

摘要

Telomere integrity is critical for telomere function and genomic stability. We previously demonstrated that non-erythroid a-spectrin (alISp) is present in mammalian cell nuclei where it is important in repair of DNA interstrand cross-links (ICLs) andchromosome stability. We now demonstrate that alISp is also important for telomere maintenance after ICL damage. It localizes to telomeres in S phase after ICL damage where it has enhanced association with TRF1 and TRF2 and is required for recruitment ofthe ICL repair protein, XPF, to damage-induced foci at telomeres. In telomerase-positive normal cells depleted of alISp by siRNA or in Fanconi anemia, complementation group A (FA-A) cells, where alISp levels are 35-40% of normal, ICL damage results in failure of XPF to localize to telomeres, markedly increased telomere dysfunction-induced foci, followed by catastrophic loss of telomeres. Restoration of alISp levels to normal in FA-A cells corrects these deficiencies. Our studies demonstrate that alISpis critical for repair of DNA ICLs at telomeres, likely by facilitating the recruitment of repair proteins similar, but not identical, to its proposed role in repair of DNA ICLs in genomic DNA and that this function in turn is critical for telomere maintenance after DNA ICL damage.