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 Cell8: 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.



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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

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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]