The Apollo 5′ Exonuclease Functions Together with TRF2 to Protect Telomeres from DNA Repair

SummaryA major issue in telomere research is to understand how the integrity of chromosome ends is preserved 1 and 2. The human telomeric protein TRF2 coordinates several pathways that prevent checkpoint activation and chromosome fusions 3, 4, 5, 6, 7, 8 and 9. In this work, we identified hSNM1B [10], here named Apollo, as a novel TRF2-interacting factor. Interestingly, the N-terminal domain of Apollo is closely related to that of Artemis, a factor involved in V(D)J recombination and DNA repair [11]. Both proteins belong to the β-CASP metallo-β-lactamase family of DNA caretaker proteins 12 and 13. Apollo appears preferentially localized at telomeres in a TRF2-dependent manner. Reduced levels of Apollo exacerbate the sensitivity of cells to TRF2 inhibition, resulting in severe growth defects and an increased number of telomere-induced DNA-damage foci and telomere fusions. Purified Apollo protein exhibits a 5′-to-3′ DNA exonuclease activity. We conclude that Apollo is a novel component of the human telomeric complex and works together with TRF2 to protect chromosome termini from being recognized and processed as DNA damage. These findings unveil a previously undescribed telomere-protection mechanism involving a DNA 5′-to-3′ exonuclease.