DNA Repair Mechanisms in Cancer: Understanding BRCA, Homologous Recombination, and PARP Inhibitors for FRCR Part 1

DNA repair mechanisms are fundamental to understanding cancer biology and modern targeted therapies. For FRCR Part 1 candidates, mastering these pathways is essential, as questions frequently test knowledge of repair mechanisms, their clinical relevance, and therapeutic exploitation.

Overview of DNA Damage and Repair Pathways

Cells face constant DNA damage from endogenous sources (reactive oxygen species, replication errors) and exogenous factors (ionizing radiation, chemotherapy). The major repair pathways include:

Base Excision Repair (BER): Repairs small base modifications and single-strand breaks (SSBs). PARP1 plays a crucial role in recognizing DNA nicks and recruiting repair machinery.

Nucleotide Excision Repair (NER): Repairs bulky DNA adducts such as UV-induced pyrimidine dimers. Defects cause xeroderma pigmentosum.

Mismatch Repair (MMR): Corrects replication errors and base mismatches. Defects cause Lynch syndrome (hereditary non-polyposis colorectal cancer) and microsatellite instability.

Homologous Recombination (HR): Error-free repair of double-strand breaks (DSBs) using the sister chromatid as a template. Requires BRCA1, BRCA2, and RAD51.

Non-Homologous End Joining (NHEJ): Rapid but error-prone repair of DSBs that does not require a homologous template.

The BRCA1/BRCA2 Pathway

BRCA1 and BRCA2 are tumour suppressors essential for homologous recombination. Germline mutations confer high lifetime risk of breast (up to 70%) and ovarian cancer (up to 40%).

BRCA1 Functions:

• Promotes 5' to 3' resection of DSB ends to generate single-stranded DNA (ssDNA) overhangs
• Facilitates loading of RAD51 recombinase onto ssDNA
• Involved in cell cycle checkpoint activation

BRCA2 Functions:

• Directly binds and delivers RAD51 to sites of DNA damage
• Controls RAD51 filament formation on ssDNA
• Essential for strand invasion during HR

Cells lacking functional BRCA1/2 cannot perform error-free HR repair and must rely on error-prone mechanisms like NHEJ, leading to genomic instability and cancer predisposition.

Synthetic Lethality and PARP Inhibitors

Synthetic lethality occurs when simultaneous loss of two genes causes cell death, while loss of either alone is tolerable. This principle underpins PARP inhibitor therapy.

Mechanism of Action:

• PARP1 is critical for single-strand break repair via BER
• PARP inhibition leads to persistent SSBs that become DSBs during replication
• Normal cells repair DSBs via HR using intact BRCA pathways
• BRCA-deficient cancer cells cannot repair DSBs and undergo cell death

PARP Trapping: Beyond catalytic inhibition, PARP inhibitors "trap" PARP1 on DNA, creating cytotoxic PARP-DNA complexes that obstruct replication forks. Trapping potency varies among agents, with talazoparib showing the strongest trapping ability.

Approved PARP Inhibitors:

• Olaparib (Lynparza) - first approved 2014
• Rucaparib (Rubraca)
• Niraparib (Zejula)
• Talazoparib (Talzenna)

Clinical trials have demonstrated significant progression-free survival benefits. The SOLO-1 trial showed olaparib extended median progression-free survival to 56 months in BRCA-mutated ovarian cancer maintenance therapy, compared to 13.8 months with placebo.

BRCAness and Beyond BRCA Mutations

The concept of "BRCAness" describes tumours with HR deficiency (HRD) despite lacking BRCA1/2 mutations. Other genes causing HRD include:

• PALB2 (Partner and Localizer of BRCA2)
• RAD51C, RAD51D
• ATM, ATR
• CHEK2

These tumours may also respond to PARP inhibitors, expanding the potential patient population beyond those with germline BRCA mutations.

Clinical Applications for FRCR Candidates

PARP Inhibitor Indications:

• BRCA-mutated ovarian cancer (maintenance and treatment)
• BRCA-mutated breast cancer
• BRCA-mutated pancreatic cancer
• BRCA-mutated prostate cancer

Integration with Radiotherapy: BRCA-deficient cells show increased sensitivity to ionizing radiation due to impaired DSB repair. This has implications for radiation dose and fractionation in BRCA mutation carriers.

Key Exam Points

• HR is the error-free pathway for DSB repair requiring BRCA1, BRCA2, and RAD51
• BRCA1 promotes end resection; BRCA2 loads RAD51 onto ssDNA
• PARP inhibitors exploit synthetic lethality in BRCA-deficient cells
• PARP trapping contributes significantly to cytotoxicity
• BRCAness tumours with HRD may also respond to PARP inhibition
• MMR deficiency causes microsatellite instability and Lynch syndrome

Understanding these mechanisms is essential not only for exam success but also for appreciating how molecular biology translates into clinical practice in modern oncology.