What is homologous
recombination deficiency?
To understand HRD, start with the repair process it describes.
Then see where that repair can fail, and how the failure is measured.
01 / HRR
Homologous Recombination Repair
Homologous recombination repair (HRR) is a high-fidelity DNA repair process that uses a homologous DNA template to restore damaged DNA.
Homologous recombination deficiency (HRD) describes impaired function of this process. BRCA1 and BRCA2 are important parts of the machinery, but studying HRD extends beyond checking these two genes.[1][2]
Keep three questions separate
- CauseWhat disrupted the repair machinery?
- FunctionIs homologous recombination still functional?
- EvidenceHow do we detect HRD?
02 / The repair process
How homologous recombination works, in brief.
Homologous recombination repairs a double-strand break by copying an intact homologous template. Resection of the broken ends exposes 3′ single-stranded tails, which RPA coats. BRCA2 helps RAD51 replace RPA and form a filament that invades the template, forming a D-loop; DNA synthesis primed by the invading strand then extends it along the template. [3][4]
03 / From repair to deficiency
What changes when HR fails?
The animation follows a successful repair. HRD means that the cell’s capacity to carry out homologous recombination is impaired. A defect can affect an early preparation step or the later use of a template. The examples below locate possible bottlenecks; they do not all occur in every HR-deficient tumour.
BRCA2 supports RAD51 loading
BRCA2-mediated loading impaired
RPA occupies the exposed single-stranded DNA. In this model, the early resection actors leave the scene so the change in DNA occupancy is easier to follow.
Both views start after resection, with RPA on the exposed DNA. Advance one step to see where BRCA2-mediated RAD51 loading makes the routes diverge.
This comparison isolates one BRCA2 repair function. Purified BRCA2 enables RAD51 to replace RPA on single-stranded DNA; in a BRCA2-mutated ovarian cancer cell line, RAD51 foci were severely impaired. The comparison does not model every BRCA2 variant, all forms of HRD, alternative repair or cell fate. The two panels share a narrative timeline, not a biological clock. Jensen et al. · 2010 Sakai et al. · 2009
Read the comparison and other points of failure Mechanisms & evidence
Steps 03–05 · Prepare Expose the DNA ends
With functional HREnd resection exposes single-stranded DNA, creating the substrate for the next repair steps.
A possible bottleneckIn BRCA1-deficient experimental models, 53BP1-dependent protection of the broken ends can restrict resection and impair HR. Other changes in the cell can modify this effect.
Bunting et al. · 2010Steps 06–09 · Find a template Build the RAD51 filament
With functional HRBRCA2 helps RAD51 assemble on single-stranded DNA. The filament supports pairing with a homologous template.
A possible bottleneckPurified BRCA2 enables RAD51 to replace RPA on single-stranded DNA. In a BRCA2-mutated ovarian cancer cell line, RAD51 foci were severely impaired and returned when secondary mutations restored BRCA2.
Jensen et al. · 2010 Sakai et al. · 2009Beyond the animation · Consequences Repair through a different route
With functional HRIn the route illustrated above, DNA synthesis copies the template and the extended strand returns to complete repair.
A possible consequenceCells with impaired HR may depend more on alternative repair. Experiments in HR-deficient ovarian cancer cells identified a dependency on polymerase θ, associated with error-prone end joining.
Ceccaldi et al. · 2015
A gene alteration suggests a cause. A genomic scar records accumulated changes. A functional assay probes a cellular response.
Explore what each approach measuresRepair capacity can also change over time. In BRCA2-mutated ovarian cancer models, secondary mutations restored BRCA2 function and HR. A tumour’s mutation history therefore needs to be distinguished from its current repair capability. [6]
These are mechanistic examples, not predictions for an individual variant or tumour. The comparison isolates two bottlenecks, a BRCA2-mediated loading defect and 53BP1-restricted resection after BRCA1 loss; other forms of HRD can affect different parts of repair.
04 / Reading the evidence
Three views of the same question.
Different approaches look at the genes involved, patterns in the tumour genome, or a cellular response. Read an HRD result together with the method that produced it. [1][8][2]
Repair machinery
Sequencing can identify alterations in genes such as BRCA1 or BRCA2. The biological effect and tumour context matter.
Genomic evidencePatterns of damage
Genomic scar approaches quantify patterns such as loss of heterozygosity, telomeric allelic imbalance and large-scale transitions.
Genomic scar studyA cellular response
RAD51-based assays examine whether cells form nuclear RAD51 foci under defined assay conditions. Sample quality and assay criteria matter.
Functional assay study05 / The HGSOC connection
Why this matters in ovarian cancer.
High-grade serous ovarian cancer (HGSOC) is the focus of this wiki. In its 2011 analysis, TCGA found evidence suggesting HR defects in about half of the tumours studied. That is a finding in a defined cohort, rather than a universal rate for every assay or population. [1]
Repair defects also motivated a therapeutic idea: exploit the dependencies left behind when a pathway fails. In 2005, PARP inhibitors were found to be synthetically lethal with defects in BRCA1 or BRCA2. [9] They are relatively non-toxic to normal cells but strikingly cytotoxic to HR-defective cells, particularly those impaired in BRCA1 or BRCA2. [10]
See a liquid biopsy study during PARP inhibitor therapy Explore my liquid biopsy research06 / Limits
What this page does not claim.
This page does not claim that:
- a pathogenic BRCA1 or BRCA2 variant shows that homologous recombination is lost in a given tumour today;
- a positive genomic-scar result shows that homologous recombination is deficient now: a scar records accumulated changes, not the current state of repair;
- the three ways of measuring HRD (genes, genomic scars, functional assays) agree with one another;
- any of the experiments cited here predicts the response of an individual patient;
- the repair route described is the only outcome of homologous recombination, or that it happens in tumour cells exactly as drawn.
Follow the evidence
References & further reading
- TCGA · 2011Integrated genomic analyses of ovarian carcinoma
- van Wijk et al. · 2020The RECAP Test Rapidly and Reliably Identifies Homologous Recombination-Deficient Ovarian Carcinomas
- Paliwal et al. · 2014Human RECQ5 helicase promotes repair of DNA double-strand breaks by synthesis-dependent strand annealing
- Jensen et al. · 2010Purified human BRCA2 stimulates RAD51-mediated recombination
- Bunting et al. · 201053BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks
- Sakai et al. · 2009Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma
- Ceccaldi et al. · 2015Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair
- Marquard et al. · 2015Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs
- Lord, Tutt & Ashworth · 2026Two decades of PARP inhibitor synthetic lethality in cancer
- Jackson & Bartek · 2009The DNA-damage response in human biology and disease
Working draft for the HGSOC wiki.