Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

  title={Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging},
  author={James E. Cleaver and Ingrid Revet},
  journal={Mechanisms of Ageing and Development},
Tumour predisposition and cancer syndromes as models to study gene–environment interactions
Tumour predisposition syndromes in which cancers arise at an accelerated rate and in different organs provide a unique opportunity to examine how gene–environment interactions influence cancer risk when the initiating genetic defect responsible for malignancy is known.
Current and emerging roles of Cockayne syndrome group B (CSB) protein.
This review focuses on the diverse roles played by CSB in cellular pathways that enhance genome stability, providing insight into the molecular features of this complex premature aging disease.
Disorders of nucleotide excision repair.
  • I. Rapin
  • Medicine, Biology
    Handbook of clinical neurology
  • 2013
Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity
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.
Lack of XPC leads to a shift between respiratory complexes I and II but sensitizes cells to mitochondrial stress
The results show that XPC deficiency leads to alterations in mitochondrial redox balance with a CI/CII shift as a possible adaptation to lower CI activity, but at the cost of sensitizing XP-C cells to mitochondrial oxidative stress.
Increased risk of internal tumors in DNA repair-deficient xeroderma pigmentosum patients: analysis of four international cohorts
The results are of particular importance for the physicians to help in early prevention and detection of internal tumors in their XP patients because the age of XP population is increasing due to better sun-protection and knowledge of the disease.
Markers of Aging in Cells of Patients with Cockayne Syndrome. General and Individual Differences
It was shown that the cells of patients with Cockayne syndrome have pronounced signs of accelerated aging in all studied markers, which allowscockayne syndrome to be a true progeria and cell lines obtained from patients as model objects for studying the processes of aging and testing geroprotectors.
Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance
A comprehensive analysis of all DNA repair mutant mouse models has been completed in order to assess the importance of haploinsufficiency for these genes, bringing to light a clear role for haplo insufficiency in disease predisposition.
Diagnosis of Xeroderma Pigmentosum and Related DNA Repair-Deficient Cutaneous Diseases.
  • J. Cleaver
  • Medicine, Biology
    Current medical literature. Dermatology
  • 2008
The relative incidence of the various forms of skin cancers in XP patients is similar to that in the general population, and UVB (280–320 nm) is the shorter wavelength radiation in sunlight that is responsible for most sun-induced cancers in thegeneral population, as well as inXP patients.


Elevated oxidative stress in patients with ataxia telangiectasia.
Results indicate that ATM might play an important role in the maintenance of cell homeostasis in response to oxidative damage, and a better control of levels of reactive oxygen species could be a rational foundation of therapeutic intervention to help alleviate some of the symptoms associated with AT.
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.
Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8‐hydroxyguanine and 8‐hydroxyadenine resulting from oxidative stress
It is suggested that the cells from CS patients accumulate oxidatively induced specific DNA base lesions, especially after oxidative stress, a deficiency in cellular repair of oxidative DNA damage might contribute to developmental defects in CS patients.
The role of CSA in the response to oxidative DNA damage in human cells
These findings support the hypothesis that defective repair of oxidative DNA damage is involved in the clinical features of CS patients and provide the first in vivo evidence that CSA protein contributes to prevent accumulation of various oxidized DNA bases.
A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis
It is concluded that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension, and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage and genetics.
Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.
It is shown that organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected.
Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice.
Premature Aging in Mice Deficient in DNA Repair and Transcription
It is hypothesized that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.
Cerebellar neurodegeneration in human hereditary DNA repair disorders