DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection

Hereditary renal cell carcinoma (RCC) is caused by germline mutations in a subset of genes, including VHL, MET, FLCN, and FH. However, many familial RCC cases do not harbor mutations in the known predisposition genes. Using Whole Exome Sequencing, we identified two germline missense variants in the DCLRE1B/Apollo gene (Apollo^N246I and Apollo^Y273H) in two unrelated families with several RCC cases. Apollo encodes an exonuclease involved in DNA Damage Response and Repair (DDRR) and telomere integrity. We characterized these two functions in the human renal epithelial cell line HKC8. The decrease or inhibition of Apollo expression sensitizes these cells to DNA interstrand crosslink damage (ICLs). HKC8 Apollo^-/- cells appear defective in the DDRR and present an accumulation of telomere damage. Wild-type and mutated Apollo forms could interact with TRF2, a shelterin protein involved in telomere protection. However, only Apollo^WT can rescue the telomere damage in HKC8 Apollo^-/- cells. Our results strongly suggest that Apollo^N246I and Apollo^Y273H are loss-of-function mutants that cause impaired telomere integrity and could lead to genomic instability. Altogether, our results suggest that mutations in Apollo could induce renal oncogenesis.