# Homologous recombination
**Homologous recombination** (HR) is a [DNA repair](https://www.edgepedia.org/dna-repair) mechanism in which an intact homologous donor duplex, usually a sister chromatid, is used to guide DNA synthesis across a double-strand break (DSB) gap, restoring the original sequence rather than merely rejoining broken ends.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3632057/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/) It is one of four major pathways that repair double-strand breaks in cells, alongside classical non-homologous end joining (NHEJ), alternative end joining (a-EJ), and single-strand annealing (SSA).[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7062608/) HR also functions in [DNA replication](https://www.edgepedia.org/dna-replication), meiotic chromosome segregation, and telomere maintenance.[4](https://www.nature.com/articles/nrm2008)
| Key fact | Detail |
|---|---|
| Defining feature | An intact homologous donor duplex guides DNA synthesis across the break gap, so the original sequence is restored[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3632057/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/) |
| Homology requirement | Typically more than 100 bp of homology, versus more than 50 bp for SSA, 2 to 20 bp for a-EJ, and 1 to 4 bp of terminal microhomology for NHEJ[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/) |
| Prerequisite step | Extensive 5′ to 3′ end resection by the CtIP and MRN (MRE11–RAD50–NBS1) complex generates single-stranded DNA at the break ends[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7062608/) |
| Central enzyme | The recombinase RAD51, a RecA homolog, catalyzes homologous pairing and DNA strand exchange[5](https://www.nature.com/articles/nrm1127) |
| Key mediator | The BRCA2 tumor suppressor loads RAD51 onto single-stranded DNA; BRCA1 favors DSB resection[6](https://www.nature.com/articles/s41388-025-03583-x.pdf) |
| Cell-cycle dependence | NHEJ accounts for nearly all DSB repair outside S and G2 phases, when no sister chromatid is available for HR[7](https://www.jbc.org/article/S0021925820338096/pdf) |
| Clinical relevance | Defects in HR, especially BRCA1/2 mutations, sensitize tumors to PARP inhibitors through synthetic lethality[8](https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02355-1) |
## Position among repair pathways
A double-strand break cuts the DNA molecule into two parts, and cells have developed two broad solutions to the problem: directly bridging the two free ends, as NHEJ does, or using sequence homology to restore the missing information, as HR does.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10528545/) In contrast to HR, which usually restores the original sequence by copying from another DNA molecule, NHEJ restores the structural integrity of the DNA but not typically its original sequence.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/)
Pathway choice is largely dictated by homology availability and end resection. NHEJ requires either no microhomology or, more often, 1 to 4 bp of terminal microhomology; a-EJ typically requires microhomology of at least 2 bp and less than 20 bp; SSA requires homology of typically more than 50 bp; and the homology requirement for HR is typically more than 100 bp.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/) The exposure of terminal homology depends on the balance between end protection and nucleolytic resection: proteins such as 53BP1, RIF1, the shieldin complex, the CST complex, and polymerase-α protect ends from extensive resection and favor NHEJ, whereas CtIP and the MRN complex carry out the extensive 5′ to 3′ resection that generates the single-stranded DNA needed for a-EJ, SSA, and HR.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7062608/)
## Mechanism
**Resection and filament assembly.** After a break is recognized, resection leaves a long 3′ single-stranded overhang.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10528545/) The recombinases then act: there are two eukaryotic recombinases, RAD51 and DMC1, both related to the bacterial recombinase RecA, and RAD51 is needed for mitotic and meiotic HR whereas DMC1 functions only during meiosis.[4](https://www.nature.com/articles/nrm2008) All the recombinases form a helical filament on single-stranded DNA, the presynaptic filament, whose assembly requires ATP and is facilitated by recombination mediators, including the yeast Rad52 protein and the human BRCA2 tumor suppressor.[4](https://www.nature.com/articles/nrm2008) RAD51 catalyzes homologous pairing and strand exchange in species from yeast to humans.[5](https://www.nature.com/articles/nrm1127)
**Homology search and D-loop formation.** The presynaptic filament can pair to homologous sequences elsewhere in the genome and form a displacement loop (D-loop), followed by DNA repair synthesis that retrieves sequence information from the donor.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC8519636/) In the double-strand-break repair (DSBR) pathway, this process creates a DNA intermediate containing two Holliday junctions, four-way junctions between the recombining duplexes; resolution of this intermediate can produce crossover recombinants carrying a reciprocal exchange of chromosome arms.[4](https://www.nature.com/articles/nrm2008) In synthesis-dependent strand annealing (SDSA), the invading strand is instead displaced and anneals to the other end of the break, producing a non-crossover repair.[4](https://www.nature.com/articles/nrm2008)
**Regulation by helicases.** DNA helicases regulate HR at several levels. The yeast Sgs1 and human BLM helicases mediate dissolution of the double Holliday junction to yield non-crossover recombinants, and the yeast Srs2 helicase attenuates HR by dismantling the Rad51 presynaptic filament.[4](https://www.nature.com/articles/nrm2008) This regulation matters because HR is indispensable for genome integrity but must be restrained to avoid deleterious events.[4](https://www.nature.com/articles/nrm2008)
## Biological roles
HR has an important role in the repair of damaged chromosomes, in preventing the demise of damaged replication forks, in meiotic chromosome segregation, and in telomere maintenance.[4](https://www.nature.com/articles/nrm2008) DSBs caused by ionizing radiation and other DNA-damaging agents are strong inducers of HR, and programmed HR processes such as meiotic recombination and yeast mating-type switching are initiated through deliberate DSB formation.[4](https://www.nature.com/articles/nrm2008)
Crossovers are crucial for chromosome segregation at meiosis I, but their formation is suppressed in mitotic cells because crossovers involving repetitive genome sequences carry an inherent risk of chromosome rearrangements.[4](https://www.nature.com/articles/nrm2008) HR provides an efficient and faithful pathway of repair, especially in replicating cells, in which it plays a major role in tumor avoidance.[5](https://www.nature.com/articles/nrm1127) Outside S and G2 phase, when no sister chromatid is available, NHEJ is the major pathway used to correct spurious DSBs.[7](https://www.jbc.org/article/S0021925820338096/pdf) • [9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10528545/)
## BRCA proteins and the HR machinery
The BRCA tumor suppressor network is built around the recombinase. BRCA1 favors resection of DSBs and the loading of RAD51; BRCA2 and PALB2 load RAD51 on the single-stranded DNA; the RAD51 paralogs RAD51C, RAD51D, and [XRCC2](https://www.edgepedia.org/xrcc2) assist RAD51 stability and dynamics, stabilize the ssDNA/RAD51 filament, and extend the intermediates; and the MRN subunits MRE11, RAD50, and NBN initiate DSB resection.[6](https://www.nature.com/articles/s41388-025-03583-x.pdf) BRCA1 and BRCA2 colocalize with RAD51 in DNA-damage-induced nuclear foci, and BRCA2 has been shown to interact directly with RAD51.[5](https://www.nature.com/articles/nrm1127) Mutations in BRCA2, which has a mediator function in HR, lead to cancer formation.[4](https://www.nature.com/articles/nrm2008)
## Clinical relevance
**PARP inhibitors and synthetic lethality.** PARP inhibitors have changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations, by exploiting synthetic lethality, the principle that genetic defects rendering cells vulnerable to a drug can be therapeutically exploited.[8](https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02355-1) Cancers with higher rates of homologous recombination deficiency are more sensitive to PARP inhibitors for this reason.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC11016131/pdf/nihms-1935796.pdf) Resistance develops through mechanisms that include restoration of homologous recombination repair, and overcoming such resistance is an active area of clinical research.[8](https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02355-1)
**Genome engineering.** Because HR proteins are mainly expressed in the G2 phase of the cell cycle, homology-directed repair-based gene editing is difficult in postmitotic cells such as neurons and cardiac myocytes, and CRISPR-mediated homologous recombination is used to produce genome-edited model organisms in research settings.[12](https://stacks.cdc.gov/view/cdc/30309/cdc_30309_DS1.pdf) • [13](https://www.nei.nih.gov/research-and-training/research-labs-and-branches/genetic-engineering-core) In mammalian cells, small molecules that inhibit NHEJ proteins, enhance HR protein function, or arrest the cell cycle in HR-dominant phases are studied as agents to transiently increase HR-mediated genome editing.[14](https://arxiv.org/abs/2308.15510)
## References
1. [Repair of Double-Strand Breaks by End Joining, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3632057/)
2. [The molecular basis and disease relevance of non-homologous DNA end joining, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8063501/)
3. [Non-homologous DNA end joining and alternative pathways to double-strand break repair, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7062608/)
4. [Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nature Reviews Molecular Cell Biology 7, 739–750 (2006)](https://www.nature.com/articles/nrm2008)
5. [West, S. C. Molecular views of recombination proteins and their control. Nature Reviews Molecular Cell Biology 4, 435–445 (2003)](https://www.nature.com/articles/nrm1127)
6. [RAD51-mediated homologous recombination is a pro-tumour driver pathway, Oncogene](https://www.nature.com/articles/s41388-025-03583-x.pdf)
7. [JBC Thematic Minireview: DNA double-strand break repair and pathway choice](https://www.jbc.org/article/S0021925820338096/pdf)
8. [Clinical approaches to overcome PARP inhibitor resistance, Molecular Cancer (2025)](https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02355-1)
9. [Structure and Mechanism in Non-Homologous End Joining, DNA Repair (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10528545/)
10. [One end to rule them all: NHEJ and HR at DNA double-strand breaks, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8519636/)
11. [PARP Inhibitors: A Review of the Pharmacology, Pharmacokinetics, and Pharmacogenetics, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11016131/pdf/nihms-1935796.pdf)
12. [Development and Applications of CRISPR-Cas9 for Genome Engineering, CDC Stacks](https://stacks.cdc.gov/view/cdc/30309/cdc_30309_DS1.pdf)
13. [Genetic Engineering Core, National Eye Institute](https://www.nei.nih.gov/research-and-training/research-labs-and-branches/genetic-engineering-core)
14. [Improving homology-directed repair by small molecule agents for genetic engineering in unconventional yeast, arXiv](https://arxiv.org/abs/2308.15510)
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*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Classical and non-Mendelian inheritance*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license