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

  title={Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity},
  author={James E. Cleaver and Ernest T. Lam and Ingrid Revet},
  journal={Nature Reviews Genetics},
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… 
Pigmentation abnormalities in nucleotide excision repair disorders: Evidence and hypotheses
In this review, the role of the DDR network in the manifestation of pigmentary abnormalities in NER and DSB disorders is discussed with a special emphasis on NER disorders.
Hypomorphic PCNA mutation underlies a human DNA repair disorder.
A syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity is described, resulting from a homozygous missense sequence alteration of the proliferating cell nuclear antigen.
DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease.
Diseases associated with defective responses to DNA damage.
A selection of novel congenital human disorders with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways are described, describing how they were identified, how genotype informs phenotype, and how these defects contribute to growing understanding of genome stability pathways.
Nucleotide excision repair genes shaping embryonic development
The current knowledge on genes that function in NER that also affect embryonic development are reviewed, in particular the development of a fully functional nervous system.
A unified model for the molecular basis of Xeroderma pigmentosum-Cockayne Syndrome
This work characterizes Rad3/XPD mutations in Saccharomyces cerevisiae and human cells and proposes a model compatible with all XP/CS cases and the current bibliography.
Oxidative and energy metabolism as potential clues for clinical heterogeneity in nucleotide excision repair disorders.
In addition to their well-characterized role in the NER signaling pathway, NER factors seem to be important in biological processes that are not directly associated with DNA damage responses, including mitochondrial function and redox homeostasis.


Cancer in xeroderma pigmentosum and related disorders of DNA repair
Nucleotide-excision repair diseases exhibit cancer, complex developmental disorders and neurodegeneration, and complex clinical phenotypes might result from unanticipated effects on other genes and proteins.
Deletion of 5′ sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome
Clinical and molecular data of two severely affected Cockayne patients with undetectable CSB protein and mRNA and new hypotheses are required to account for the pathophysiology of Cockayne syndrome, at the crossroads between DNA repair and transcription.
Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality.
The essential function of the XPD protein in mammals and in cellular viability is established and is consistent with the notion that only subtle XPD mutations are found in XP, XP/Cockayne syndrome, and trichothiodystrophy patients.
Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome.
The sites of the mutations in the CSB gene were analyzed in 16 patients to determine the spectrum of mutations in this gene and to see whether the nature of the mutation correlates with the type and severity of the clinical symptoms.
A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy.
Activated oncogenes in human skin tumors from a repair-deficient syndrome, xeroderma pigmentosum.
It is proposed that the presence of several oncogene alterations in the same tumor could be due to the high amount of UV-induced DNA lesions found in the exposed skin cells, in the absence of efficient repair.
A temperature-sensitive disorder in basal transcription and DNA repair in humans
The findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes in humans, which previously were only known in lower organisms.
hRAD30 mutations in the variant form of xeroderma pigmentosum.
It is shown that XP variant (XP-V) cell lines harbor nonsense or frameshift mutations in hRAD30, the human counterpart of yeast RAD30, and this suggests that error-free replication of UV lesions by hRad30 plays an important role in minimizing the incidence of sunlight-induced skin cancers.
Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity.
Eight causative mutations are identified, of which four have not been described before, either in TTD or XP cases, supporting the hypothesis that the mutations responsible for TTD are different from those found in other pathological phenotypes.