Rapid compensatory evolution within a multiprotein complex preserves telomere integrity

Intragenomic conflict with selfish genetic elements spurs adaptive changes in subunits of essential multiprotein 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 melanogaster multiprotein complex that protects telomeres from lethal fusions despite one subunit, HOAP (HP1/ORC-associated protein), evolving adaptively to restrict selfish telomeric retrotransposons. Swapping HOAP's adaptively evolving interaction partner, HipHop (HP1-HOAP-interacting protein), between closely related Drosophila species disrupted HOAP recruitment to the telomere, leading to lethal telomere fusions. Reverting six adaptively evolving sites on HipHop's interaction surface with HOAP, 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.