Abstract
Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human disorders caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated ageing. All three syndromes include developmental abnormalities, indicating an important role for optimal transcription and for NER in protecting against spontaneous DNA damage during embryonic development. Here, we review the current knowledge on genes that function in NER that also affect embryonic development, in particular the development of a fully functional nervous system.
Highlights
The disclosure of the intricacies of DNA repair has been made possible by the early description of human familial disease syndromes and by the more recent investigation of their genetic and molecular bases
The role of large protein complexes and the significance of their cellular localization are common features of many of the biochemical mechanisms involved. One of these DNA repair mechanisms is nucleotide excision repair (NER), which is responsible for removing a large variety of DNA lesions, including those helix-destabilizing DNA lesions induced by UV radiation [4]
Alterations in NER genes are associated with autosomal recessive human diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD), whose symptoms involve skin cancer and developmental and neurological symptoms
Summary
The genome of all living beings exists in a dynamic equilibrium between ongoing DNA damage and reversal of the damage by DNA repair pathways. The role of large protein complexes and the significance of their cellular localization are common features of many of the biochemical mechanisms involved One of these DNA repair mechanisms is nucleotide excision repair (NER), which is responsible for removing a large variety of DNA lesions, including those helix-destabilizing DNA lesions induced by UV radiation [4]. The defining CS factors are Cockayne syndrome A (CSA) and B (CSB) proteins, the CS phenotype can result from specific mutations in some XP genes (XPB, XPD and XPG). Another related factor, named XPA-binding protein 2 (XAB2), has been isolated as an XPA-interacting protein in a yeast two-hybrid screen. Whereas XP is a disease more directly linked with the NER core reaction, CS is intrinsically connected with the transcriptional side of DNA repair and general transcription defects [21,22]
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