Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal–Hreidarsson syndrome
Résumé
Telomeres, the protein–DNA complexes at the ends of linear chro- mosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the β-lactamase/β-CASP family. Impaired telomere protection in humans causes dyskeratosis con- genita and Hoyeraal–Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique Apollo splice variant (designated Apollo-Δ) in fibroblasts from a patient with HH syndrome. Apollo- Δ generates a dominant negative form of Apollo lacking the telomeric repeat- binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Δ hampers the proper replication of telomeres, leading to major telomeric dys- function and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results iden- tify Apollo as a crucial actor in telomere maintenance in vivo, in- dependent of its function as a general DNA repair factor.