image: (a) Telomeric DNA damage and tracing model schematic. (b) DDR machinery redistribution in reproductive aging
Credit: ©Science China Press
Recently, the research team led by Prof. Junjiu Huang from Sun Yat-sen University, in collaboration with Prof. Fenghua Liu’s team at Guangdong Women and Children Hospital, published a study titled "Insufficient telomeric DNA damage response promotes chromosomal instability in aged oocytes" in Science Bulletin. The study elucidates the crucial mechanism of telomeric DDR in mammalian oocytes and demonstrates that inadequate telomeric DDR is a key factor driving chromosomal instability in aged oocytes.
By analyzing clinically discarded human oocyte samples, the team found that nearly half of spontaneous DNA damage in germinal vesicle (GV)-stage oocytes localized to telomeres, with damage levels accumulating with donor age. To investigate whether and how mammalian oocytes respond to telomeric DNA damage, researchers established simultaneous telomeric damage induction and tracing by integrating CRISPR/Cas9 with the TTALE system (a 3D genome imaging system developed by Prof. Guanghui Liu). Moreover, through genome-wide CUT&Tag profiling of γH2AX occupancy, they validated the specificity of the DNA damage model. This model revealed that telomeric damage directly compromises oocyte quality, manifesting as chromosomal instability, reduced maturation rates, and chromosome misalignment.
Mammalian oocytes are meiotically arrested at the GV stage for months or even decades, potentially resulting in the accumulation of telomeric or non-telomeric DNA damage. Interestingly, the study revealed that telomeric DNA damage accelerated telomere movement in mouse GV oocytes, indicating DDR activation. Mechanistically, RPA32 and RAD51 were recruited to damaged telomeres, and contributed to promoting break-induced telomere synthesis (BITS) along with ATR and PARP1. Notably, limited RNF8 recruitment impaired 53BP1 localization at damaged telomeres. Consequently, Cas9-induced telomeric damage failed to trigger telomere fusion, demonstrating that oocytes predominantly utilize homologous recombination for telomeric DDR. This repair bias likely evolved to ensure efficient and high-fidelity genetic transmission during reproduction.
Importantly, although overall RAD51-mediated DDR activity remained unchanged in aged oocytes, elevated non-telomeric DNA damage diverted the limited DDR capacity away from telomeres. This competition resulted in insufficient BITS at telomeres and elevated aneuploidy in aged oocytes, ultimately compromising chromosomal stability and oocyte quality.
Unlike somatic cells, mammalian oocytes maintain meiotic arrest throughout their prolonged lifespan without proliferative capacity. Consequently, replication-dependent telomere shortening is negligible, indicating that accumulated telomeric DNA damage serves as the primary driver of oocyte aging. This study establishes three fundamental advances: (1) the first direct evidence linking telomeric DNA damage to oocyte genomic instability and quality decline; (2) demonstration that telomeric DDR in GV oocytes recruits RAD51 to activate BITS; (3) identification of insufficient telomeric DDR as an exacerbating factor for chromosomal instability during reproductive aging. Collectively, these findings provide transformative insights into oocyte telomere biology and create a conceptual foundation for potential anti-aging interventions.
Funding:
The National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, Fundamental Research Funds for the Central Universities, Sun Yat-sen University, and the Guangdong Province Excellent Youth Team Project.