This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example, "dna_repair_synthetic_lethality#PARP and Platinum Synthetic Lethality"). The module is intended for BRCA1/2-mutant, PALB2-mutant, HRD-positive, and related FA/BRCA-deficient cancers, including ovarian, breast, prostate, pancreatic, and selected DNA-repair-deficient tumors. Treatments such as PARP inhibitors and platinum chemotherapy should use target_mechanisms to connect to the synthetic-lethality node when the disorder entry represents that therapeutic vulnerability. Acquired resistance nodes can conform to the POLQ/error-prone repair or restored-HRR nodes when supported by tumor-specific evidence.
HRR or FA/BRCA Repair Deficiency
trigger
Loss of BRCA1, BRCA2, PALB2, RAD51 paralogs, or other FA/BRCA pathway components impairs high-fidelity homologous recombination repair. This creates the initiating repair-deficient state that drives genomic instability and makes the tumor dependent on backup DNA repair processes.
Downstream
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Replication-Associated DNA Damage Accumulation
HRR and FA/BRCA pathway loss leaves replication-associated breaks and crosslink-derived lesions insufficiently repaired.
Show evidence (2 references)
"Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed as an anticancer synthetic lethal therapeutic strategy for tumors with impaired homologous recombination DNA repair, based on a synthetic lethal effect."
Review evidence establishes impaired homologous recombination DNA repair as the repair-deficient state that creates PARP-inhibitor synthetic lethality.
"The Fanconi anemia (FA) pathway repairs DNA interstrand crosslinks (ICLs), and deficiencies in this pathway cause a fraction of breast and ovarian cancers as well as FA, a chromosome instability syndrome characterized by bone marrow failure and cancer predisposition."
The FA-CHKREC Boolean network paper summarizes the FA/BRCA pathway as an interstrand-crosslink repair system whose deficiency contributes to cancer and chromosomal instability.
Replication-Associated DNA Damage Accumulation
amplifier
PARP-dependent single-strand break repair, interstrand-crosslink repair, and RAD51-mediated homologous recombination converge at stressed replication forks. When HRR or FA/BRCA repair is deficient, single-strand breaks, interstrand crosslinks, and stalled forks generate persistent DNA damage and replication-fork collapse.
Downstream
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PARP and Platinum Synthetic Lethality
The accumulated damage state creates a therapeutic vulnerability to PARP inhibition and DNA-damaging platinum agents.
Show evidence (2 references)
"Poly(ADP-ribose) polymerase (PARP) is involved in single-strand DNA break base excision repair."
Review evidence supports PARP-dependent single-strand break repair as a repair process whose inhibition becomes consequential in HRR-deficient cells.
"Consistent with a role in the repair of ICLs by homologous recombination (HR), knockdown of MCM8 or MCM9 significantly reduces HR repair efficiency."
Cell-based experiments link interstrand-crosslink repair to homologous recombination efficiency and RAD51 recruitment at DNA damage sites.
PARP and Platinum Synthetic Lethality
therapeutic vulnerability
In HRR-deficient tumor cells, PARP inhibition blocks single-strand break repair and can convert unresolved lesions into double-strand breaks that cannot be repaired faithfully. Platinum agents add crosslinking lesions that similarly stress HRR and FA/BRCA repair. The combined logic is synthetic lethality: a tumor-specific repair defect converts otherwise tolerable DNA damage into selective tumor-cell death.
Downstream
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Error-Prone End Joining and POLQ-Mediated Repair
Treatment pressure can select cells that survive by using mutagenic repair alternatives or by generating reversion events.
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Restored HRR and Acquired Resistance
Resistant clones can restore homologous recombination repair and lose the synthetic-lethal vulnerability.
Show evidence (2 references)
"PARP inhibition causes synthetic lethality in breast cancers associated with germline BRCA1 and BRCA2 mutations and is routinely used in clinical practice for metastatic breast cancer."
Review evidence directly supports the synthetic-lethal relationship between PARP inhibition and BRCA-associated HRR deficiency.
"BC resulting from a germline BRCAm (gBRCAm) has distinct clinical characteristics along with increased sensitivity to DNA-damaging agents such as poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies, and potentially decreased sensitivity to cyclin-dependent kinase 4..."
Review evidence supports the broader therapeutic-vulnerability pattern: germline BRCA-mutated breast cancers show sensitivity to both PARP inhibitors and platinum-based chemotherapy.
Restored HRR and Acquired Resistance
consequence
Resistant tumor subclones can acquire BRCA1, BRCA2, or PALB2 reversion mutations that restore open reading frames or otherwise restore HRR function. Once HRR is restored, PARP inhibitor or platinum sensitivity is reduced and the original synthetic-lethal relationship is weakened.
Show evidence (2 references)
"No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression."
TRITON2 post-progression plasma analysis documents acquired BRCA reversion mutations after rucaparib treatment.
"These data support the need for restored HRR function in PARPi resistance."
TOPARP-B resistance analysis directly supports restored homologous recombination repair as a requirement for PARP-inhibitor resistance.