Rapid compensatory evolution within a multi-protein complex preserves telomere integrity

Intra-genomic conflict with selfish genetic elements spurs adaptive changes in subunits of essential, multi-protein complexes. Whether and how these adaptive changes disrupt interactions within such complexes and threaten their essential functions remains unexplored. To investigate this, we exploited a Drosophila multi-protein complex that protects telomeres from lethal fusions despite one subunit, HOAP, evolving adaptively to restrict selfish telomeric retrotransposons. Swapping HipHop, the adaptively evolving interaction partner of HOAP, between Drosophila species disrupted HOAP recruitment to the telomere, leading to lethal telomere fusions. Reverting six adaptively evolving sites on the protein-protein interaction surface of HipHop, or introducing its conspecific HOAP, restored protein recruitment, telomere protection, and viability. Our in vivo, evolution-guided manipulations illuminate how intermolecular compensatory evolution preserves essential functions in the face of antagonism by selfish elements.