Diseases of DNA Double-Strand Break Repair

Germline mutations in DSBR genes are responsible for several developmental disorders associated with increased predisposition to cancer:

Ataxia telangiectasia, characterized by cerebellar neurodegeneration, hematologic malignancies and immunodeficiency, is usually caused by germline mutations in the ATM gene;

Nijmegen breakage syndrome 1, characterized by microcephaly, short stature and recurrent infections, is caused by germline mutations in the NBN (NBS1) gene;

Seckel syndrome, characterized by short stature, skeletal deformities and microcephaly, is caused by germline mutations in the ATR or RBBP8 (CtIP) genes.

Heterozygous germline mutations in BRCA1, BRCA2 or PALB2 cause the hereditary breast and ovarian cancer syndrome (HBOC), while homozygous germline mutations in BRCA2 and PALB2 cause Fanconi anemia, a developmental disorder characterized by short stature, microcephaly, skeletal defects, bone marrow failure, and predisposition to cancer.

Somatic mutations in DSBR genes are also frequently found in sporadic cancers.

The pathways "Defective DNA double strand break response due to BRCA1 loss of function" describes defects in DSB response caused by loss-of-function mutations in BRCA1 which prevent the formation of the BRCA1:BARD1 complex.

The pathway "Defective DNA double strand break response due to BARD1 loss of function" describes defects in DSB response caused by loss-of-function mutations in BARD1, the heterodimerization partner of BRCA1, which prevent the formation of the BRCA1:BARD1 complex.

The pathway "Defective homologous recombination repair (HRR) due to BRCA1 loss of function" describes defects in HRR caused by loss-of-function mutations in BRCA1 that impair its association with PALB2.

The pathway "Defective homologous recombination repair (HRR) due to BRCA2 loss of function" describes defects in HRR caused by loss-of-function mutations in BRCA2 that impair either it association with SEM1 (DSS1), its translocation to the nucleus, its binding to RAD51, or its binding to PALB2.

The pathway "Defective homologous recombination repair (HRR) due to PALB2 loss of function" describes defects in HRR caused by loss-of-function mutations in PALB2 that impair its association with BRCA2/RAD51/RAD51C.

For review, please refer to McKinnon and Caldecott 2007, Keijzers et al. 2017, and Jachimowicz et al. 2019.