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Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity

Key Points

  • Mutations in genes on the nucleotide excision repair pathway are associated with diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD), that involve skin cancer and developmental and neurological symptoms.

  • DNA damage in non-transcribed regions of the genome is recognized by the combined action of the DNA damage-binding 2 (DDB2) and XPC recognition proteins. Structural studies show that the binding mechanism does not depend on the chemical nature of the damaged bases but only on the loss of hydrogen bonding, which produces local single-stranded regions and the extrusion of the damage to an extrahelical position.

  • The repair of damage in transcriptionally active regions is faster than in non-transcribed regions and is associated with the functions of the CSA (also known as ERCC8) and CSB (also known as ERCC6) genes. Mutations in this pathway are associated with photosensitivity and neurodegeneration.

  • The neurodegeneration in patients with defective DNA repair is associated in part with internally generated DNA damage. One potential source is reactive oxygen released from mitochondria; other sources could be circulating steroids and other reactive metabolites.

  • Mutations in the XPD protein, which is a component of the TFIIH transcription factor, result in a complex set of diseases, including XP, TTD and XP combined with CS. The complexity is thought to arise because mutations affect different functions of XPD, such as the helicase activity, the stability of TFIIH and the interactions of XPD with other transcription factor components.

  • Mice with individual nucleotide excision repair genes knocked out or with specific mutations inserted display a cancer-prone phenotype but weakly display a neurological phenotype, unless combined transcription-coupled repair and global genomic repair crosses are made.

Abstract

Mutations in genes on the nucleotide excision repair pathway are associated with diseases, such as xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, that involve skin cancer and developmental and neurological symptoms. These mutations cause the defective repair of damaged DNA and increased transcription arrest but, except for skin cancer, the links between repair and disease have not been obvious. Widely different clinical syndromes seem to result from mutations in the same gene, even when the mutations result in complete loss of function. The mapping of mutations in recently solved protein structures has begun to clarify the links between the molecular defects and phenotypes, but the identification of additional sources of clinical variability is still necessary.

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Figure 1: The xeroderma pigmentosum C protein.
Figure 2: The Cockayne syndrome B protein.
Figure 3: Functional motifs and mutation sites of archaeal xeroderma pigmentosum D.
Figure 4: Lifespan and clinical features of xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy.

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Acknowledgements

The work described here was supported by grant 1R01NS052781 from the US National Institute of Neurological Disorders and Stroke. We are also grateful to the XP Society, the XP Family Support Group and the Luke O'Brien Foundation for their continued support and encouragement.

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Cockayne Syndrome Network

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Information on human DNA repair genes

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XP Family Support Group

Glossary

Archaea

A group of single-celled microorganisms that lack a nucleus or any other organelles. They have an independent evolutionary history, show distinctive biochemistry and are now classified as a separate domain from eukaryotes and bacteria.

Cachectic dwarfism

Dwarfism associated with loss of weight, muscle atrophy, fatigue, weakness and substantial loss of appetite. Cachexia is the loss of body mass that cannot be reversed nutritionally even with caloric supplements.

Retinopathy

Non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.

Microcephaly

A neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex.

Purkinje cells

The primary integrative neurons of, and sole output from, the cerebellar cortex. The cerebellum has an important role in the integration of sensory perception, coordination and motor control.

Ichthyosis

A heterogeneous family of skin disorders characterized by dry, thickened, scaly or flaky skin. The term arises from a resemblance to the scales on a fish.

Cyclobutane pyrimidine dimer

The most common photoproduct induced in DNA by shortwave UV-B and UV-C wavelengths. Adjacent pyrimidines on the same DNA strand are linked by new bonds between the 5–5 and 6–6 positions and the normal 5=6 double bonds become single.

Ubiquitylation

The conjugation of ubiquitin, which is a highly conserved 76-amino-acid protein, to another protein. Monoubiquitylation is involved in cell signalling, whereas polyubiquitylation can mark proteins for destruction.

[6–4] photoproduct

An ultraviolet radiation-induced DNA lesion formed between the C-4 position of a 5′ pyrimidine and the C-6 position of an adjacent pyrimidine. This occurs approximately one-third as frequently as the cyclobutane pyrimidine dimer but causes greater structural distortion.

SWI/SNF proteins

(Switch/sucrose non-fermentable proteins). Chromatin remodelling multiprotein complexes. This protein family was initially identified in yeast, but related complexes exist in mammals and are involved in gene activation and repression.

Poly(ADP-ribosyl)ation

A post-translational modification that involves the addition of one or more ADP-ribose moieties to proteins. It is involved in cell signalling and the control of many processes, including DNA repair and apoptosis. The modification generally results in reduced protein activity.

Base excision repair

A process for replacing damaged single nucleotides that involves DNA glycosylases.

Reactive oxygen species

Ions or small molecules, including oxygen ions, free radicals and inorganic and organic peroxides, that are highly reactive owing to the presence of unpaired valence shell electrons. They are a by-product of the normal metabolism of oxygen and have important roles in cell signalling. Increased levels, due to environmental stress, can result in damage to cells.

Transposon

A mobile DNA element that can move in the genome. Transposons can be used for various applications, including insertional mutagenesis, gene identification, gene tagging and DNA sequencing.

Glycation end product

The product of a chain of chemical reactions after an initial glycation reaction by which sugar molecules become bound to a protein or lipid molecule without the controlling action of an enzyme.

Globus pallidus

A subcortical structure of the brain that is a major element of the basal ganglia system.

Helicase

An enzyme that separates the two nucleic acid strands in a double helix, which results in the formation of regions of ssDNA or ssRNA.

Ischaemia–reperfusion injury

Injury to the epithelial cells of blood vessels and surrounding tissue that occurs during reoxygenation after the transient interruption of blood flow. It is thought to be caused by the rapid changes in tissue oxygenation.

Glycosylase

DNA glycosylases are a family of enzymes that are involved in base excision repair. They remove the damaged nitrogenous base by flipping it out of the double helix. This is followed by cleavage of the N-glycosidic bond. The sugar–phosphate backbone remains intact, creating an apurinic or apyrimidinic site.

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Cleaver, J., Lam, E. & Revet, I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet 10, 756–768 (2009). https://doi.org/10.1038/nrg2663

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