Insufficient telomeric DNA damage response promotes chromosomal instability in aged oocytes

Area of Science:

• Reproductive Biology
• Genetics
• Cellular Biology

Background:

• Chromosomal instability in oocytes contributes to female reproductive aging.
• The telomeric DNA damage response (DDR) is crucial for maintaining genomic stability.
• Mechanisms of telomeric damage response in oocytes are not well understood.

Purpose of the Study:

• To investigate how oocytes respond to telomeric DNA damage.
• To elucidate the role of DDR in oocyte aging and quality.
• To identify key molecular players in telomeric DDR in oocytes.

Main Methods:

• Observation of telomeric DNA damage in aged human germinal vesicle (GV) oocytes.
• Development of a CRISPR/Cas9-induced telomeric DNA damage model in mouse oocytes.
• Analysis of molecular recruitment (RPA32, RAD51, RNF8, 53BP1) and DNA repair pathways (ATR, PARP1) at telomeres.

Main Results:

• Aged oocytes accumulate telomeric DNA damage.
• Telomeric damage triggers break-induced telomere synthesis (BITS) via RPA32, RAD51, ATR, and PARP1 recruitment.
• Aged oocytes show impaired telomeric DDR and BITS, with DDR machinery preferentially engaging non-telomeric regions.
• Telomeric damage accelerated telomere movement but did not cause telomere fusion.

Conclusions:

• Telomeric DDR activates BITS through recruitment of factors like RAD51.
• Insufficient telomeric DDR and BITS in aged oocytes contribute to increased chromosomal instability.
• Understanding telomeric DDR is critical for addressing female reproductive aging.