Simian-specific SAGE1 enhances germline genome stability by promoting homologous recombination

DNA damage response (DDR) is essential for maintaining germline genome integrity to ensure the accurate transmission of genetic information. Most DDR genes emerged at an early evolutionary stage and had been acquired by the time the Vertebrata group first arose. Here, we identify a spermatogonia-enriched protein encoded by SAGE1, a simian-specific X-linked gene, as a recently evolved DDR regulator that plays an essential role in maintaining germline genome stability. The unique SAGE1-specific exon repeats endow SAGE1 with the ability of promoting germline genome integrity via the error-free homologous recombination (HR) pathway by orchestrating crucial repair steps through multiple interactions with key HR factors, such as CtIP, SOSS and NuA4 complexes. Thus, SAGE1 represents an ‘upgrade’ to the existing landscape of DDR by introducing an additional layer of regulation. Our findings provide novel insights into the evolutionary adaptations underlying distinctive traits of simians, suggesting that SAGE1 might be one of the key genetic underpinnings for the enhanced germline genome integrity in the simian lineage.