Diseases of DNA repair

Stable Identifier
Homo sapiens
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Germline and somatic defects in genes that encode proteins that participate in DNA repair give rise to genetic instability that can lead to malignant transformation or trigger cellular senescence or apoptosis. Germline defects in DNA repair genes are an underlying cause of familial cancer syndromes and premature ageing syndromes. Somatic defects in DNA repair genes are frequently found in tumors. For review, please refer to Tiwari and Wilson 2019.

We have so far annotated diseases of mismatch repair, diseases of base excision repair and diseases of DNA double-strand break repair.

Defects in mammalian DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, and MSH6) result in microsatellite instability (MSI) and reduced fidelity during replication and repair steps. Defective variants of MMR genes are associated with sporadic cancers with hypermutation phenotypes as well as hereditary cancer syndromes such as Lynch syndrome (hereditary non-polyposis colorectal cancer) and constitutional mismatch repair deficiency syndrome (CMMRD). MSI is an important predictor of sensitivity to cancer immunotherapy as the high mutational burden renders MSI tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors (Mandal et al. 2019). For review, please refer to Pena-Diaz and Rasmussen 2016, Sijmons and Hofstra 2016, Tabori et al. 2017, Baretti and Le 2018.

Germline mutations, single nucleotide polymorphisms (SNPs) and somatic mutations in several genes involved in base excision repair (BER), a DNA repair pathway where a damaged DNA base is excised and replaced with a correct base, are involved in the development of cancer and several oxidative stress-related diseases. For review, please refer to Fu et al. 2012, Fletcher and Houlston 2010, Brenerman et al. 2014, Patrono et al. 2014, and D'Errico et al. 2017.

Germline mutations in genes involved in repair of DNA double-strand breaks (DSBs) are the underlying cause of several cancer predisposition syndromes, some of which also encompass developmental disorders associated with immune dysfunction, radiosensitivity and neurodegeneration. Somatic mutations in genes involved in DSB repair also occur in sporadic cancers. 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
20414203 Architecture of inherited susceptibility to common cancer

Houlston, RS, Fletcher, O

Nat. Rev. Cancer 2010
31374202 DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging

Wilson, DM, Tiwari, V

Am. J. Hum. Genet. 2019
22237395 Balancing repair and tolerance of DNA damage caused by alkylating agents

Fu, D, Samson, LD, Calvo, JA

Nat. Rev. Cancer 2012
25355293 Base excision repair capacity in informing healthspan

Wilson, DM, Brenerman, BM, Illuzzi, JL

Carcinogenesis 2014
26708048 Approaches to diagnose DNA mismatch repair gene defects in cancer

Peña-Diaz, J, Rasmussen, LJ

DNA Repair (Amst.) 2016
31048490 Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response

Riaz, N, Hechtman, JF, Bartlett, B, Srivastava, R, Mandal, R, Diaz, LA, Lee, KW, Chan, TA, Havel, JJ, Kuo, F, Blecua, P, Krishna, C, Durham, JN, Samstein, RM, Morris, LG, Sabio, EY, Weinhold, N, Zehir, A, Ma, X, Ramaswamy, AT, Le, DT, Makarov, V, Wang, H, Middha, S

Science 2019
25493225 Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity

Testa, A, Patrono, C, Sterpone, S, Cozzi, R

World J Clin Oncol 2014
28572265 Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

Hansford, JR, Tabori, U, Achatz, MI, Plon, SE, Kratz, CP, Frebourg, T, Brugières, L

Clin. Cancer Res. 2017
17887919 DNA strand break repair and human genetic disease

Caldecott, KW, McKinnon, PJ

Annu Rev Genomics Hum Genet 2007
26746812 Review: Clinical aspects of hereditary DNA Mismatch repair gene mutations

Hofstra, RMW, Sijmons, RH

DNA Repair (Amst.) 2016
27932076 Single nucleotide polymorphisms in DNA glycosylases: From function to disease

Simonelli, V, Pascucci, B, Baccarini, S, Parlanti, E, Dogliotti, E, Fortini, P, D'Errico, M

Free Radic. Biol. 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
29117491 Monogenic Diseases of DNA Repair

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

N Engl J Med 2017
29669262 DNA mismatch repair in cancer

Le, DT, Baretti, M

Pharmacol. Ther. 2018
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Name Identifier Synonyms
genetic disease DOID:630
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