DNA Repair: Disorders


Deoxyribonucleic acid (DNA) inside cells is being damaged continually. Cells have evolved a series of complex mechanisms to repair all types of damage. Deficiencies in these repair pathways can result in several different genetic disorders. In many cases these are associated with a greatly elevated incidence of specific cancers. Other disorders do not show increased cancer susceptibility, but instead they present with neurological abnormalities or immune defects. Features of premature ageing also often result. These disorders indicate that DNA repair and damage response processes protect us from cancer and are important for the maintenance of a healthy condition.

Key Concepts:

  • DNA is damaged continually from both endogenous and exogenous sources.

  • Cells have evolved many different ways for repairing different types of damage.

  • Genetic defects in these pathways result in different disorders.

  • Defective DNA repair often results in an increased mutation frequency and consequent elevated incidence of cancer. Many of the DNA repair disorders are highly cancer‐prone.

  • The central nervous system appears to be particularly sensitive to DNA breaks. Several disorders caused by defective break repair are associated with neurological abnormalities including mental retardation, ataxia and microcephaly.

  • Development of immunological diversity uses some of the enzymes required to repair double‐strand breaks. Disorders caused by defects in this process are associated with immune deficiencies.

Keywords: UV light; xeroderma pigmentosum; ataxia telangiectasia; cancer; immunodeficiency; DNA repair

Figure 1.

Different steps in nucleotide excision repair (NER), showing the involvement of the different xeroderma pigmentosum (XP) and Cockayne syndrome (CS) proteins. Modified from Volker M, Mone MJ, Karmakar P, et al. (2001) Sequential assembly of the nucleotide excision repair factors in vivo. Molecular Cell 8: 213–224, with permission from Elsevier.

Figure 2.

Patients with (a) xeroderma pigmentosum, (b) trichothiodystrophy and (c) Cockayne syndrome.

Figure 3.

The steps of double‐strand break repair by nonhomologous end‐joining.

Figure 4.

DNA damage signalling. The red arrows indicate ATM‐dependent phosphorylation events. The mediators enhance ATM‐dependent signalling. Phosphorylated H2AX is referred to as γH2AX.

Figure 5.

The steps of Base excision repair. represents a damaged or inappropriate base, some examples of which are shown on the following line. These bases are cleaved of the backbone by the indicated glycosylases. Disorders resulting from enzymatic defects are indicated in parentheses below the enzyme.



Bose T and Gerton JL (2010) Cohesinopathies, gene expression, and chromatin organization. Journal of Cell Biology 189: 201–210.

van der Burg M, Ijspeert H, Verkaik NS et al. (2009) A DNA‐PKcs mutation in a radiosensitive T‐B‐SCID patient inhibits Artemis activation and nonhomologous end‐joining. Journal of Clinical Investigation 119: 91–98.

Caldecott KW (2008) Single‐strand break repair and genetic disease. Nature Reviews. Genetics 9: 619–631.

Chu WK and Hickson ID (2009) RecQ helicases: multifunctional genome caretakers. Nature Reviews. Cancer 9: 644–654.

Digweed M and Sperling K (2004) Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double‐strand breaks. DNA Repair (Amsterdam) 3: 1207–1217.

Fousteri M and Mullenders LH (2008) Transcription‐coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. Cell Research 18: 73–84.

Fousteri M, Vermeulen W, van Zeeland AA and Mullenders LH (2006) Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo. Molecular Cell 23: 471–482.

Gudmundsdottir K and Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25: 5864–5874.

Hashimoto S and Egly JM (2009) Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Human Molecular Genetics 18: R224–230.

Jiricny J (2006) The multifaceted mismatch‐repair system. Nature Reviews. Molecular Cell Biology 7: 335–346.

Kraemer KH, Lee MM and Scotto J (1987) Xeroderma pigmentosum. Cutaneous, ocular and neurologic abnormalities in 830 published cases. Archives of Dermatology 123: 241–250.

Lavin MF (2008) Ataxia‐telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nature Reviews. Molecular Cell Biology 9: 759–769.

Lehmann AR (2001) The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes & Development 15: 15–23.

Lieber MR (2010) The mechanism of double‐strand DNA break repair by the nonhomologous DNA end‐joining pathway. Annual Review of Biochemistry 79: 181–211.

Ma Y, Pannicke U, Schwarz K and Lieber MR (2002) Hairpin opening and overhang processing by an Artemis/DNA‐dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108: 781–794.

Masutani C, Kusumoto R, Iwai S and Hanaoka F (2000) Accurate translesion synthesis by human DNA polymerase η. EMBO Journal 19: 3100–3109.

McCulloch SD, Kokoska RJ, Masutani C et al. (2004) Preferential cis‐syn thymine dimer bypass by DNA polymerase η occurs with biased fidelity. Nature 428: 97–100.

Meindl A, Hellebrand H, Wiek C et al. (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nature Genetics 42: 410–414.

Moldovan GL and D'Andrea AD (2009) How the fanconi anemia pathway guards the genome. Annual Review of Genetics 43: 223–249.

Moshous D, Callebaut I, de Chasseval R et al. (2001) Artemis, a novel DNA double‐strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105: 177–186.

Nance MA and Berry SA (1992) Cockayne Syndrome: Review of 140 cases. American Journal of Medical Genetics 42: 68–84.

Nouspikel T (2009) DNA repair in mammalian cells: Nucleotide excision repair: variations on versatility. Cellular and Molecular Life Sciences 66: 994–1009.

O'Driscoll M (2009) Mouse models for ATR deficiency. DNA Repair (Amsterdam) 8: 1333–1337.

O'Driscoll M, Cerosaletti KM, Girard P‐M et al. (2001) DNA Ligase IV mutations identified in patients exhibiting development delay and immunodeficiency. Molecular Cell 8: 1175–1185.

O'Driscoll M, Ruiz‐Perez VL, Woods CG, Jeggo PA and Goodship JA (2003) A splicing mutation affecting expression of ataxia‐telangiectasia and Rad3‐related protein (ATR) results in Seckel syndrome. Nature Genetics 33: 497–501.

Rass U, Ahel I and West SC (2007) Defective DNA repair and neurodegenerative disease. Cell 130: 991–1004.

Stefanini M, Botta E, Lanzafame M and Orioli D (2010) Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amsterdam) 9: 2–10.

Stewart GS, Maser RS, Stankovic T et al. (1999) The DNA double‐strand break repair gene hMRE11 is mutated in individuals with an ataxia‐telangiectasia‐like disorder. Cell 99: 577–587.

Stracker TH, Theunissen JW, Morales M and Petrini JH (2004) The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amsterdam) 3: 845–854.

Taylor AM, Groom A and Byrd PJ (2004) Ataxia‐telangiectasia‐like disorder (ATLD)‐its clinical presentation and molecular basis. DNA Repair (Amsterdam) 3: 1219–1225.

Vaz F, Hanenberg H, Schuster B et al. (2010) Mutation of the RAD51C gene in a Fanconi anemia‐like disorder. Nature Genetics 42: 406–409.

Wu L and Hickson ID (2003) The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426: 870–874.

Zlatanou A and Stewart GS (2010) A PIAS‐ed view of DNA double strand break repair focuses on SUMO. DNA Repair (Amsterdam) 9: 588–592.

Further Reading

Fernandez‐Capetillo O (2010) Intrauterine programming of ageing. EMBO Report 11: 32–36.

Friedberg EC, Walker GC, Siede W et al. (2005) DNA Repair and Mutagenesis, 2nd edn. Washington DC: ASM Press.

Hoeijmakers JH (2009) DNA damage, aging, and cancer. New England Journal of Medicine 361: 1475–1485.

Ochs HD, Smith CIE and Puck JM (eds) (2006) Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, 2nd edn. Oxford: Oxford University Press.

O'Driscoll M and Jeggo PA (2006) The role of double‐strand break repair – insights from human genetics. Nature Reviews. Genetics 7: 45–54.

Web Links

Ataxia, oculomotor apraxia type 1 MIM 208920

Ataxia‐telangiectasia like disorder MIM 604391

Ataxia‐telangiectasia MIM 208900

Bloom Syndrome MIM 210900

Cockayne syndrome Type A MIM 216400

Cockayne syndrome Type B; MIM 133540

Cornelia de Lange syndrome MIM 122470

Fanconi Anemia MIM 227650

Nijmegen Breakage Syndrome MIM 251260

Roberts syndrome MIM 268300

Rothmund‐Thomson Syndrome MIM 268400

Seckel syndrome MIM 210600

Spinocerebellar ataxia with axonal neuropathy; SCAN1 MIM 607250

Werner Syndrome MIM 277700

Xeroderma pigmentosum Group A MIM 278700

Xeroderma pigmentosum Group B MIM 610651

Xeroderma pigmentosum Group C MIM 278720

Xeroderma pigmentosum Group D MIM 278730

Xeroderma pigmentosum Group E MIM 278740

Xeroderma pigmentosum Group F MIM 278760

Xeroderma pigmentosum Group G MIM 278780

Xeroderma pigmentosum variant MIM 278750

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lehmann, Alan R, and O'Driscoll, Mark(Oct 2010) DNA Repair: Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005999.pub2]