A Novel Role of DELTEX2 in Maintaining Genomic Stability of Granulosa Cells During Ovarian Aging

Abstract

ABSTRACT Genomic instability is a key driver of ovarian aging, impairing granulosa cell (GC) function and diminishing ovarian reserve. However, the regulatory mechanisms underlying GC genomic homeostasis remain poorly defined. This study investigates the novel role of DELTEX2 (DTX2) in maintaining GC genomic stability and its underlying mechanism in the DNA damage response during ovarian aging. Our data show that telomere length was significantly shortened in both ovarian tissues and isolated GCs from aged mice. Meanwhile, DTX2 was markedly downregulated in aged ovaries, while it was highly expressed in GCs. To investigate the functional role of DTX2 in GCs, we performed knockdown and overexpression experiments in the human ovarian granulosa‐like tumor cell line (KGN). DTX2 knockdown compromises genomic stability in GCs, as evidenced by reduced telomerase reverse transcriptase (TERT) expression, accelerated telomere shortening, elevated micronucleus formation, and ultimately suppressed cell proliferation coupled with G2/M phase cell cycle arrest. DTX2 overexpression upregulates TERT transcription and effectively mitigates DNA damage, as evidenced by reduced γH2AX levels and fewer micronuclei, ultimately enhancing GC proliferation and suppressing apoptosis under H 2 O 2 ‐induced DNA damage conditions. Mechanistically, DTX2‐mediated maintenance of genomic homeostasis was found to be associated with the NOTCH2 signaling pathway. Collectively, these findings uncover a novel role of DTX in GC genomic homeostasis, which may serve as a potential therapeutic target for ovarian aging‐related dysfunction.