A study explains how a crucial protein complex that protects DNA can respond to emerging challenges while continuing to perform its core role effectively.
In Lewis Carroll’s Through the Looking-Glass, Alice finds herself trapped in an endless race with the Red Queen, running constantly but never moving ahead. “It takes all the running you can do to keep in the same place,” the Queen tells her.
“Though we typically use this metaphor to describe evolutionary arms races between hosts and parasites or hosts and pathogens, the ‘Red Queen Hypothesis’ also characterizes the ongoing battles within our genome,” says Mia Levine, a biologist at the University of Pennsylvania.
Certain regions of DNA behave in what researchers call a “selfish” way. Mobile genetic elements, for instance, have evolved the ability to shift their position within the genome by cutting or copying themselves and inserting into new sites. When this happens, they can interfere with genes or other DNA sequences that carry out important functions. To counter these disruptive elements, cells rely on molecular defenses that can recognize, silence, or physically block them.
This internal struggle raises a longstanding scientific question. How can some of the most critical and stable biological processes rely on proteins that must continually change in order to defend against ongoing genetic threats?
Protecting Chromosome Ends
Now, Levine and colleagues have demonstrated how a pair of essential protein partners navigate this challenge. The team focused on the genes in Drosophila melanogaster, fruit flies, that are responsible for creating the protective caps—telomeres—at the ends of chromosomes, which Levine likens to the plastic tips on shoelaces.
The findings, published in Science, show that while the function of these proteins—protecting the end of chromosomes—remains constant, the proteins themselves are constantly shapeshifting to fight off selfish elements.
To prevent chromosome tips from fusing—which can cause genetic instability, fertility issues, and cell and organismal death—a group of six proteins assemble into the end-protection complex to bind telomeric DNA.
Proteins Under Pressure to Change
The researchers found that two members of this complex, the HipHop protein and its binding partner HOAP, evolve far faster than the other subunits yet are indispensable for telomere protection.
“We offer a first glimpse of the fascinating biology faithfully preserved by an essential multiprotein complex whose subunits are under potent evolutionary pressure to change,” says Levine.
They tested whether these proteins have to evolve in lockstep (coevolve) to keep the complex intact by using gene editing tools to replace the native HipHop in D. melanogaster flies with the version from another closely-related fly species, D. yakuba.
The researchers found that when they engineered D. melanogaster flies to make the D. yakuba version of HipHop instead of their own version, the flies died—their cells showed rampant end-to-end chromosome fusions.
Conversely, reverting just six adaptively evolving amino acids—the building blocks of proteins—in D. yakuba HipHop back to their D. melanogaster counterparts, or introducing the D. yakuba version of HOAP, restored protein recruitment, telomere protection, and viability.
As HOAP evolves to silence internal enemies, Levine explains, the HipHop protein is forced to evolve in tandem.
How selfish DNA “antagonizes” these proteins is largely unknown, says Levine. “But similar evolutionary signatures in primates suggest this kind of compensatory evolution may be widespread and studying it could clarify how genomes retain ancient functions while adapting to ever-shifting threats.”
Reference: “Rapid compensatory evolution within a multiprotein complex preserves telomere integrity” by Sung-Ya Lin, Hannah R. Futeran, Briana N. Cruga, Andrew Santiago-Frangos and Mia T. Levine, 27 November 2025, Science.
DOI: 10.1126/science.adv0657
Funding: National Institutes of Health, Taiwanese Government Scholarship
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