Homologous recombination

Homologous recombination (HR) is a critical process in cellular DNA repair, genetic recombination, and the maintenance of genomic stability. It involves the exchange of genetic information between two similar or identical molecules of DNA. HR is essential for the repair of double-strand breaks (DSBs), the resolution of stalled replication forks, and the segregation of chromosomes during meiosis.

Mechanism

The process of homologous recombination begins with the sensing and processing of a DSB. The broken DNA ends are first resected to produce 3' single-stranded DNA (ssDNA) tails. This ssDNA is then coated by the recombinase protein RAD51, which displaces the replication protein A (RPA) and forms a nucleoprotein filament. This RAD51-ssDNA filament searches for and invades a homologous DNA duplex, forming a displacement loop (D-loop). The invading 3' end of the ssDNA then primes DNA synthesis, using the homologous strand as a template. Following DNA synthesis, the resulting joint molecules can be resolved through different pathways, leading to crossover or non-crossover outcomes.

Functions

Homologous recombination serves several vital functions in the cell:

• DNA Repair: HR is one of the main pathways for repairing DSBs, which can arise from external sources, such as ionizing radiation, or internal sources, such as replication fork collapse. By using a homologous sequence as a template for repair, HR ensures high-fidelity restoration of the original DNA sequence.

• Replication Fork Support: HR assists in the restart of stalled replication forks, a critical function for the prevention of genomic instability.

• Meiotic Recombination: During meiosis, HR facilitates the exchange of genetic material between homologous chromosomes, promoting genetic diversity in gametes.

Regulation

The regulation of homologous recombination is complex and involves numerous proteins and pathways. Key regulators include the BRCA1 and BRCA2 proteins, which play significant roles in the repair of DSBs through HR. Mutations in these genes are linked to a higher risk of breast and ovarian cancers, underscoring the importance of HR in preventing tumorigenesis.

Clinical Significance

Defects in homologous recombination can lead to genomic instability, a hallmark of cancer. Consequently, understanding HR mechanisms has implications for cancer biology and therapy. Inhibitors of proteins involved in HR, such as PARP inhibitors, have shown promise in treating cancers with HR deficiencies, exemplifying the therapeutic potential of targeting this pathway.

See Also

• DNA repair
• Genetic recombination
• RAD51
• BRCA1
• BRCA2