Key Points
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Living cells respond to DNA damage by a variety of mechanisms, including a series of biochemical pathways called DNA repair. These include three discrete pathways for the excision of damaged bases, called base excision repair, mismatch repair and nucleotide excision repair (NER).
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NER in human cells is a complex biochemical process during which a large multiprotein complex is assembled at several types of base damage. This multiprotein complex (NER machine) catalyses the excision of damaged bases as oligonucleotide fragments.
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The RNA polymerase II basal transcription factor, TFIIH, is an integral component of the NER multiprotein complex.
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NER operates somewhat differently on DNA that is transcriptionally active (transcription-coupled repair) and that which is transcriptionally silent (global genome repair).
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Defective NER in humans caused by genetically inherited mutations in NER genes results in the skin-cancer-prone disease xeroderma pigmentosum.
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Hereditary defects in transcription-coupled NER can result in a disease called Cockayne syndrome, which is characterized by severe developmental and neurological disorders.
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Mutational inactivation of certain NER genes can result in a combined syndrome of xeroderma pigmentosum and Cockayne syndrome, or in yet another disease called trichothiodystrophy, which is characterized by brittle hair and nails.
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Cockayne syndrome, combined xeroderma pigmentosum/Cockayne syndrome complex and trichothiodystrophy are not usually associated with increased cancer risk.
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Mouse mutant strains generated by targeted gene replacement have been constructed to model these human NER-defective syndromes.
Abstract
Eukaryotic cells can repair many types of DNA damage. Among the known DNA repair processes in humans, one type — nucleotide excision repair (NER) — specifically protects against mutations caused indirectly by environmental carcinogens. Humans with a hereditary defect in NER suffer from xeroderma pigmentosum and have a marked predisposition to skin cancer caused by sunlight exposure. How does NER protect against skin cancer and possibly other types of environmentally induced cancer in humans?
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Acknowledgements
I apologize to numerous colleagues for the omission of many pertinent references owing to space constraints. I also gratefully acknowledge B. Stewart for outstanding assistance with the illustrations, and L. Queimado, R. Rolig, M. Liskay and P. Modrich for critical reading of some or all of the manuscript.
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Glossary
- BASE DAMAGE
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Any change in the chemistry of the nitrogenous bases in DNA (adenine, thymine, guanine or cytosine), as well as the presence of inappropriate bases such as uracil, which is normally only in RNA.
- REPLICATION FORK
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The region of replicating DNA in which active DNA synthesis is occurring to generate two copies of the parental DNA.
- REPAIR SYNTHESIS
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A mode of DNA synthesis that is associated with DNA repair rather than with replication. Sometimes called conservative DNA synthesis to distinguish it from the semi-conservative DNA synthesis that characterizes replication.
- SEMI-CONSERVATIVE
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This term refers to the way in which double-stranded DNA is replicated in all cells. During replication, each of the parental DNA strands is partitioned to a new double-stranded DNA molecule. So one half of the parental DNA is conserved, hence semi-conservative.
- REACTIVE OXYGEN SPECIES
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(ROS). Highly reactive chemical radicals that are generated as products of oxygen degradation.
- COMPLEMENTATION GROUP
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This refers to a genetic grouping of individuals, based on the fact that cells from individuals in any complementation group cannot correct a phenotypic defect among themselves, but can correct it in cells from other groups. Individuals in a given complementation group usually carry mutations in the same gene.
- BASAL TRANSCRIPTION FACTORS
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A set of protein complexes that associate with RNA polymerase II during the initiation of all mRNA synthesis. Sometimes called general transcription factors.
- ENDONUCLEASES
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Enzymes that cut the sugar–phosphate backbone of DNA (or RNA) at sites other than the free ends of linear DNA (which are degraded by exonucleases).
- SOMATIC MUTATION THEORY
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A theory on the pathogenesis of cancer that essentially postulates that cancer in somatic cells arises from mutations. More recently, the theory has been adapted to specifically implicate mutations in oncogenes or tumour suppressor genes.
- HAPLOINSUFFICIENCY
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A phenotypic state that results from loss of one functional allele of any given gene in diploid cells. Sometimes also called allelic insufficiency.
- HPRT GENE
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A gene that encodes hypoxanthine phosphoribosyltransferase. It is a convenient marker for measuring mutation frequency in cells, because cells with a mutant HPRT gene require supplementation with 6-thioguanine to grow.
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Friedberg, E. How nucleotide excision repair protects against cancer. Nat Rev Cancer 1, 22–33 (2001). https://doi.org/10.1038/35094000
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DOI: https://doi.org/10.1038/35094000
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