Throughout evolution, the DDR has served as the genome’s guardianship system, with most of its core components established as early as the emergence of eukaryotes. Yet a thought-provoking paradox has persisted: why do primates such as humans exhibit significantly lower germline mutation rates than rodents such as mice? This cross-species difference in genome stability hints at the existence of undiscovered “evolutionary patches” in higher primates.
By systematically comparing DDR differences in spermatogonia from humans, crab-eating macaques, and mice, the team discovered that human and macaque spermatogonia exhibit significantly higher repair efficiency following DNA damage compared to their mouse counterparts. Further analysis pinpointed a previously uncharacterized gene — SAGE1 — a gene found exclusively in simians, completely absent in prosimians, rodents, and other placental mammals, and specifically expressed in spermatogonia. Functional experiments showed that SAGE1 knockdown leads to accumulated DNA damage, reduced repair efficiency, and a shift from HR toward NHEJ. Conversely, ectopic expression of human SAGE1 in mouse or Drosophila spermatogonia significantly enhanced their DNA repair capacity.
The most prominent structural feature of the SAGE1 protein is its internal tandem repeat array-SERs. Evolutionary analysis revealed that the SERs represent a unique “evolutionary innovation” specific to SAGE1 and serve as the “functional switch” for its DDR activity; deletion of the SER repeats completely abolishes the protein’s protective function. Mechanistically, the SER domain serves as a molecular platform that links multiple repair-associated proteins, achieving precise spatiotemporal coordination at DNA damage sites. Upon double-strand break (DSB) formation, SAGE1 is rapidly recruited to damage sites within 30 seconds through direct interaction between its SERs and the MRN-CtIP complex. Once at the scene, SAGE1 cooperates with CtIP to provide an “anchor” for the SOSS complex, promoting DNA end resection — a critical initiating step of homologous recombination. Simultaneously, SAGE1 interacts with the NuA4/TIP60 acetyltransferase complex, facilitating acetylation of histone H4 at lysine 16 (H4K16ac), thereby opening the chromatin “gate” for homologous recombination repair. Through these coordinated steps, SAGE1 shifts the DNA repair balance from error-prone NHEJ toward accurate HR. In SAGE1 -depleted cells, the proportion of NHEJ is significantly elevated, while RAD51-mediated HR repair is impaired — making the genome more susceptible to mutation accumulation.
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Simian-specific SAGE1 enhances germline genome stability by promoting homologous recombination
25-May-2026