BRCA1, BRCA2 and ATM genes and their roles in tumor development

1. Concept

BRCA1, BRCA2, ATM are tumor suppressors involved in homologous-recombination repair of double-strand breaks. Germline loss-of-function dramatically raises hereditary breast/ovarian cancer risk; they follow the two-hit model (inherited mutation + somatic loss of the other allele).

2. The HR repair pathway

Double-strand break (e.g. ionizing radiation) → ATM sensor kinase activated → phosphorylates BRCA1 + p53/CHK2 → BRCA1 complexes with BRCA2 + RAD51 → faithful homologous-recombination repair + cell-cycle arrest.

3. The genes

Gene	Role	Loss → cancers / syndrome
BRCA1	HR repair, recruits RAD51; cell-cycle checkpoint	Breast (incl. triple-negative), ovarian, prostate
BRCA2	Loads RAD51 onto ssDNA for HR	Breast, ovarian, pancreas, stomach
ATM	DNA-damage sensor; activates p53/CHK2 → arrest + repair	Biallelic → ataxia-telangiectasia (cerebellar ataxia, telangiectasias, radiosensitivity, immunodeficiency); ↑ breast carcinoma, leukemia/lymphoma

4. Therapeutic angle

• BRCA-deficient tumors can’t repair DSBs by HR → depend on PARP-mediated single-strand repair.
• PARP inhibitors → synthetic lethality → selective tumor-cell death.

💡 High-yield: BRCA1/BRCA2/ATM = homologous-recombination DSB repair (ATM → BRCA1 → BRCA2/RAD51). Germline loss → hereditary breast/ovarian cancer (BRCA1 → triple-negative). ATM biallelic = ataxia-telangiectasia (radiosensitive). BRCA-deficient tumors → PARP inhibitors (synthetic lethality).