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DNA Repair Synthetic Lethality Module

Pharmacology Oncology Module dna_repair_synthetic_lethality 4 disorders Pathograph 5
A conserved oncology mechanism module for tumors with impaired homologous recombination repair (HRR) or FA/BRCA pathway function. HRR-deficient cells accumulate replication-associated DNA damage and become selectively vulnerable to PARP inhibition and platinum-induced DNA lesions. Therapeutic pressure can then select escape states, including POLQ-associated microhomology-mediated repair and BRCA reversion events that restore HRR. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, preserving the conserved causal chain while substituting tumor-specific initiating genes, biomarker states, therapies, and resistance mechanisms.
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Pathophysiology Nodes

5
5 shared nodes are defined in this module.
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Cell Types

0
No cell types are annotated for this module.
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Biological Processes

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double-strand break repair via homologous recombination GO:0000724 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves decreased double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology. DECREASED interstrand cross-link repair GO:0036297 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves decreased interstrand cross-link repair (GO:0036297). GO:0036297 is a biological process from the Gene Ontology. DECREASED single strand break repair GO:0000012 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves dysregulated single strand break repair (GO:0000012). GO:0000012 is a biological process from the Gene Ontology. DYSREGULATED DNA damage response GO:0006974 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. INCREASED single strand break repair GO:0000012 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves decreased single strand break repair (GO:0000012). GO:0000012 is a biological process from the Gene Ontology. DECREASED alternative end joining GO:0097681 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased alternative end joining (GO:0097681). GO:0097681 is a biological process from the Gene Ontology. INCREASED double-strand break repair via homologous recombination GO:0000724 Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology. INCREASED
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Notes

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.
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Used By Disorder Entries

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Ewing Sarcoma via Replication Stress and Impaired Homologous Recombination → PARP and Platinum Synthetic Lethality
Fallopian Tube Cancer via Homologous Recombination Deficiency → HRR or FA/BRCA Repair Deficiency
Hereditary Breast and Ovarian Cancer Syndrome via Homologous Recombination Deficiency → HRR or FA/BRCA Repair Deficiency
Ovarian High-Grade Serous Carcinoma via Homologous Recombination Deficiency → HRR or FA/BRCA Repair Deficiency , PARP and Platinum Synthetic Lethality , POLQ-Mediated Microhomology Repair Escape → Error-Prone End Joining and POLQ-Mediated Repair , BRCA Reversion and Restored HRR Resistance → Restored HRR and Acquired Resistance
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.
Pathograph: causal mechanism network for DNA Repair Synthetic Lethality Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

5
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.
double-strand break repair via homologous recombination GO:0000724 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology. DECREASED interstrand cross-link repair GO:0036297 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interstrand cross-link repair (GO:0036297). GO:0036297 is a biological process from the Gene Ontology. DECREASED
Used by disorders
Fallopian Tube Cancer as Homologous Recombination Deficiency
Hereditary Breast and Ovarian Cancer Syndrome as Homologous Recombination Deficiency
Ovarian High-Grade Serous Carcinoma as Homologous Recombination Deficiency
Downstream
  • Replication-Associated DNA Damage Accumulation HRR and FA/BRCA pathway loss leaves replication-associated breaks and crosslink-derived lesions insufficiently repaired.
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.
single strand break repair GO:0000012 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated single strand break repair (GO:0000012). GO:0000012 is a biological process from the Gene Ontology. DYSREGULATED DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. INCREASED
replication fork GO:0005657 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves replication fork (GO:0005657). GO:0005657 is a cellular component from the Gene Ontology.
Downstream
  • PARP and Platinum Synthetic Lethality The accumulated damage state creates a therapeutic vulnerability to PARP inhibition and DNA-damaging platinum agents.
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.
single strand break repair GO:0000012 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased single strand break repair (GO:0000012). GO:0000012 is a biological process from the Gene Ontology. DECREASED double-strand break repair via homologous recombination GO:0000724 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology. DECREASED
Used by disorders
Ewing Sarcoma as Replication Stress and Impaired Homologous Recombination
Ovarian High-Grade Serous Carcinoma
Downstream
  • 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.
  • Restored HRR and Acquired Resistance Resistant clones can restore homologous recombination repair and lose the synthetic-lethal vulnerability.
Error-Prone End Joining and POLQ-Mediated Repair
adaptive escape
When canonical HRR or FA/BRCA repair is impaired, tumor cells can rely on alternative end-joining and microhomology-mediated repair. POLQ-associated repair can generate frameshift deletion-mediated reversion events under PARP-inhibitor or platinum pressure, creating a route toward acquired resistance.
alternative end joining GO:0097681 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased alternative end joining, annotated with double-strand break repair via alternative nonhomologous end joining (GO:0097681). GO:0097681 is a biological process from the Gene Ontology. INCREASED
Used by disorders
Ovarian High-Grade Serous Carcinoma as POLQ-Mediated Microhomology Repair Escape
Downstream
  • Restored HRR and Acquired Resistance Error-prone repair can generate reversion mutations that restore the reading frame of HRR genes.
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.
double-strand break repair via homologous recombination GO:0000724 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology. INCREASED
Used by disorders
Ovarian High-Grade Serous Carcinoma as BRCA Reversion and Restored HRR Resistance