The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

Area of Science:

• Cell Biology
• Genetics
• Molecular Biology

Background:

• Meiosis requires homologous chromosome pairing and synapsis for genetic stability.
• Repair of SPO11-induced double-strand breaks (DSBs) via homologous recombination is essential for normal gamete production.
• Organisms eliminate meiocytes with unrepaired DSBs or unsynapsed chromosomes to prevent genetic defects.

Purpose of the Study:

• To investigate the role of the CHK2-dependent DNA damage checkpoint in culling defective mouse oocytes.
• To understand the mechanisms underlying DSB repair and synapsis during mouse oocyte meiosis.
• To explore the contribution of intersister recombination in repairing meiotic DSBs.

Main Methods:

• Analysis of mouse oocytes with mutations in SPO11, CHEK2, and TRIP13.
• Assessment of DSB accumulation, homologous chromosome synapsis, and oocyte viability.
• Investigation of HORMAD1/2 protein localization and function on chromosome axes.
• Evaluation of fertility rescue through gene deletion (Hormad2).

Main Results:

• The CHK2-dependent DNA damage checkpoint culls mouse oocytes defective in DSB repair and/or homolog synapsis.
• The checkpoint is activated by a threshold of spontaneous DSBs (∼10) in late prophase I.
• HORMAD1/2 proteins on unsynapsed axes inhibit DSB repair.
• Hormad2 deletion rescued fertility in oocytes with a synapsis-proficient, DSB repair-defective mutation (Trip13).

Conclusions:

• The CHK2 checkpoint acts as a critical safeguard against aneuploidy by eliminating defective oocytes.
• HORMAD proteins play a key role in regulating DSB repair during meiosis.
• The findings suggest that intersister recombination is a major pathway for repairing meiotic DSBs in mice.