Homologous Recombination Mechanisms in DNA Repair Systems

Homologous recombination is a high-fidelity pathway responsible for the repair of DNA double-strand breaks and the maintenance of genome stability. The process initiates with detection of a break followed by resection to generate single-stranded DNA ends, which are then coated by recombinases that search for homologous sequences on sister chromatids. Central to this pathway is RAD51, a recombinase that forms a nucleoprotein filament on single-stranded DNA and catalyses homology search and strand invasion. Accessory factors such as BRCA2 coordinate the replacement of single-strand binding proteins with RAD51 filaments and contribute to replication fork protection under stress. Following strand invasion, DNA synthesis extends the invading strand using the homologous template, after which junctions are resolved to restore intact chromosomes. Recent advances have elucidated structural and regulatory aspects of these steps, revealing dynamic protein–DNA interactions and post-translational modifications that modulate activity. Mutations in key recombination factors underpin tumour susceptibility syndromes, emphasising the clinical relevance of understanding mechanistic details and offering routes to novel therapeutic strategies that exploit recombination defects in cancer cells.

Research from Nature Portfolio

Recent studies have illuminated the role of a DNA-binding region at the C terminus of BRCA2 in homologous recombination and replication fork preservation. Researchers identified a C-terminal Recombinase Binding (CTRB) domain that binds DNA and synergises with core BRCA2 motifs to stimulate RAD51 filament assembly on single-stranded DNA. This DNA-binding activity enhances RAD51’s strand exchange capacity and supports the displacement of single-strand binding proteins, facilitating efficient repair of double-strand breaks. Moreover, the CTRB–RAD51 interaction was shown to be essential for protecting nascent replication forks from nucleolytic degradation, thereby preventing genome instability during replication stress. These findings reveal a previously unrecognised functional plasticity in BRCA2 and clarify why deletions in the C-terminal region compromise viability and repair fidelity.

Homologous Recombination Mechanisms in DNA Repair Systems publication trend

The graph below shows the total number of articles in homologous recombination mechanisms in dna repair systems across all publications each year (not limited to Nature Index journals).

Technical terms

Homologous recombination: Error-free repair pathway that uses a homologous DNA template to mend double-strand breaks.

Double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, requiring specialised repair mechanisms.

RAD51: A recombinase protein that forms nucleoprotein filaments on single-stranded DNA to mediate homology search and strand invasion.

BRCA2: A tumour suppressor and recombination mediator that regulates RAD51 filament assembly and protects replication forks.

Replication fork: The Y-shaped structure formed during DNA replication where parental strands are unwound to serve as templates for synthesis.

References

1. DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation. Nature Communications (2023).
2. TLK1-mediated RAD54 phosphorylation spatio-temporally regulates Homologous Recombination Repair. Nucleic Acids Research (2023).
3. Visualization of direct and diffusion-assisted RAD51 nucleation by full-length human BRCA2 protein. Molecular Cell (2023).
4. Homologous recombination and the repair of DNA double-strand breaks. Journal of Biological Chemistry (2018).
5. Harnessing DNA Double-Strand Break Repair for Cancer Treatment. Frontiers in Oncology (2019).