Homologous recombination (HR) repairs DNA double-strand breaks primarily in S/G2, when a sister chromatid is available as a template. It is generally higher fidelity than end-joining pathways, although no repair process is literally error-free. BRCA1, PALB2, BRCA2 and RAD51 act at different steps. Loss of HR function can leave genomic scars and may create PARP-inhibitor vulnerability, but 'BRCAness', HRD assay results and treatment benefit are related rather than interchangeable concepts.
HR begins with DSB detection by MRN, which recruits ATM and promotes 5′→3′ DNA end resection to generate 3′ single-stranded DNA (ssDNA) overhangs. RPA covers ssDNA to prevent secondary structure formation. BRCA1 (recruited via ubiquitin/RAP80 cascade) bridges to PALB2, which recruits BRCA2. BRCA2 displaces RPA and loads RAD51 monomers onto ssDNA, forming a nucleoprotein filament. The RAD51-ssDNA filament performs strand invasion of the homologous duplex sister chromatid, using it as a template for accurate DNA synthesis before resolution and ligation.
HR begins with DSB detection by MRN, which recruits ATM and promotes 5′→3′ DNA end resection to generate 3′ single-stranded DNA (ssDNA) overhangs. RPA covers ssDNA to prevent secondary structure formation. BRCA1 (recruited via ubiquitin/RAP80 cascade) bridges to PALB2, which recruits BRCA2. BRCA2 displaces RPA and loads RAD51 monomers onto ssDNA, forming a nucleoprotein filament. The RAD51-ssDNA filament performs strand invasion of the homologous duplex sister chromatid, using it as a template for accurate DNA synthesis before resolution and ligation.
Homologous Recombination Repair
Replication protein A (RPA) coats 3′ ssDNA overhangs, preventing secondary structure and activating ATR kinase. HR is restricted to S/G2 phase by CDK1/2-mediated phosphorylation of CtIP, ensuring the sister chromatid template is present before HR is initiated.
BRCA1 (recruited via RNF168 ubiquitin cascade and RAP80) directly binds PALB2 via its coiled-coil domain. PALB2 acts as a molecular bridge to BRCA2, co-localising BRCA2 with the ssDNA substrate. This three-component assembly (BRCA1–PALB2–BRCA2) is the central scaffold of the HR repair complex.
BRCA2 (with DSS1) displaces RPA from ssDNA and loads RAD51 monomers in an ATP-dependent reaction, forming a right-handed helical RAD51-ssDNA nucleoprotein filament. This filament has the capacity to search homologous duplex DNA sequences over megabase distances.
The RAD51-ssDNA filament performs strand invasion of the intact sister chromatid at the homologous sequence, forming a displacement loop (D-loop). The 3′ ssDNA end within the D-loop serves as primer for DNA synthesis using the sister chromatid as error-free template.
DNA Pol δ/ε extends the invaded strand using the sister chromatid template. After second end capture (double-strand break repair pathway) or dissolution (synthesis-dependent strand annealing, SDSA), Holiday junctions are resolved by GEN1/MUS81-EME1 or dissolved by BLM-TOP3α-RMI1/2, restoring the original sequence with high fidelity.
Pathogenic germline variants in BRCA1, BRCA2 and several other repair genes can create inherited cancer predisposition, but risk estimates differ by gene, variant, age, sex and family history. Tumours can also acquire somatic changes or epigenetic silencing that impair HR. A genomic-scar result describes patterns accumulated over the tumour's history; it is not identical to a BRCA variant, does not establish inheritance and may not prove that HR is currently inactive.
PARP inhibition can exploit vulnerabilities associated with BRCA1/2 loss and other homologous-recombination defects through catalytic inhibition, PARP trapping and replication-associated damage. Regulatory indications differ by tumour, biomarker, germline or somatic status, prior therapy, maintenance setting and combination. An HRD score or ATM alteration alone should not be interpreted as proof of equivalent benefit across these settings.
What is the difference between HR and NHEJ for DSB repair?
Homologous recombination (HR) usually uses a sister chromatid as a template and is most available in S/G2. Non-homologous end joining (NHEJ) ligates DNA ends without a homologous template and operates more broadly across the cell cycle. HR is generally higher fidelity, while end joining can alter sequence at the junction; neither pathway is accurately described as infallible in every context.
What is PARP trapping and why does it differ from catalytic PARP inhibition?
Catalytic PARP inhibition simply reduces PARP enzymatic activity (NAD+ consumption). PARP trapping — the more cytotoxic mechanism of current PARP inhibitors — involves the inhibitor stabilising the PARP1-DNA complex after nick detection, preventing PARP release and creating a physical 'roadblock' on DNA that is lethal when encountered by a replication fork. Talazoparib is the most potent PARP trapper; niraparib and olaparib have intermediate trapping; veliparib has poor trapping despite catalytic inhibition.
Compare germline BRCA results, tumour BRCA or ATM alterations and genomic-scar HRD tests—and learn what each finding can and cannot establish.
Understand BRCA1 in homologous recombination, how germline and tumour findings differ, what HRD can and cannot establish, and why PARP evidence is context-specific.
Understand how tumor suppressor genes — including TP53, BRCA1, PTEN, and RB1 — act as the genome's brakes, and what happens when they are lost in cancer.
How ATM coordinates the DNA-damage response, what germline and tumour alterations mean, and why ATM loss is not interchangeable with BRCA deficiency.
How mismatch repair, MSI and Lynch syndrome relate—and why tumour screening, germline testing and immunotherapy evidence answer different questions.
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