Diseases of DNA Double-Strand Break Repair

Stable Identifier
Homo sapiens
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Diseases of DNA double-strand break repair (DSBR) are caused by mutations in genes involved in repair of double strand breaks (DSBs), one of the most cytotoxic types of DNA damage. Unrepaired DSBs can lead to cell death, cellular senescence, or malignant transformation.

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.

We have so far annotated defects in DSB response caused by loss-of-function mutations in BRCA1 and its heterodimerization partner BARD1, which prevent the formation of the BRCA1:BARD1 complex.

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

Literature References
PubMed ID Title Journal Year
29117491 Monogenic Diseases of DNA Repair

Scheibye-Knudsen, M, Keijzers, G, Bakula, D

N Engl J Med 2017
31116084 DNA double-strand break repair pathway choice - from basic biology to clinical exploitation

Reinhardt, HC, Jachimowicz, RD, Goergens, J

Cell Cycle 2019
17887919 DNA strand break repair and human genetic disease

Caldecott, KW, McKinnon, PJ

Annu Rev Genomics Hum Genet 2007
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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