A single BRCA2 BRC repeat supports viability while multiple repeats ensure resilience under stress.

Area of Science:

• Genetics
• Molecular Biology
• Genomics

Background:

• BRC repeats are crucial for BRCA2 function in homologous recombination (HR).
• Mammals typically possess eight BRC repeats, but their necessity is unclear.
• Previous research suggested functional redundancy among BRC repeats.

Purpose of the Study:

• To investigate the biological significance of multiple BRC repeats in BRCA2.
• To determine if a single BRC repeat is sufficient for BRCA2-mediated DNA repair.
• To explore the role of BRC repeat number in maintaining genome stability.

Main Methods:

• Generated knock-in mice with a single BRC repeat (BRC2 or BRC4).
• Assessed cell viability, RAD51 loading, and PARP inhibitor resistance in mouse embryonic stem cells (mESCs).
• Analyzed genomic instability and RAD51 recruitment in embryonic fibroblasts under varying oxygen and oxidative stress conditions.

Main Results:

• A single BRC repeat (BRC2 or BRC4) supported mESC viability, RAD51 loading, and resistance to PARP inhibitors.
• Knock-in mice with a single BRC repeat were viable and fertile.
• Embryonic fibroblasts with a single BRC repeat showed genomic instability and impaired RAD51 recruitment, particularly under oxidative stress.

Conclusions:

• One BRC repeat is sufficient for essential BRCA2 functions under normal physiological conditions.
• Multiple BRC repeats likely confer an evolutionary advantage by ensuring genome stability during oxidative stress.
• The number of BRC repeats is critical for robust DNA repair under challenging environmental conditions.