42 Deficiencies in DNA repair and its clinical impacts

Abstract

All organisms have an evolved an intricate network of DNA repair systems, that permits elimination of virtually any type of DNA injury. Genetic defects in DNA repair pathways or in damage-induced cell cycle arrest result in genetic instability and a strong predisposition to cancer. Examples of this class of human syndromes are xeroderma pigmentosum (XP), Bloom's syndrome, Fanconi's anaemia, and ataxia telangiectasia. One of the major damage repair pathways is nucleotide excision repair (NER). This system. removes a broad spectrum of DNA lesions among which the mam UV-induced injury and bulky chemical adducts. Three NER-deficient human syndromes characterized by marked photosensitivity are known: XP, Cockayne syndrome (CS) and trichothiodystrophy (TTD). XP patients show pigmentation abnormalities and an over 1000 × increased risk of skin cancer caused by defects in one of at least 7 genes (XPA to XPG). CS displays sun sensitivity and overall developmental impairment. Two responsible genes are known: CSA and CSB. TTD is characterized by brittle hair, ichthyosis and many CS symptoms. The NER defect in TTD is due to mutations in TTDA, XPB or XPD. There are no indications for an increased risk of cancer in CS and TTD. Some patients show a combined XP + CS picture. They have been assigned to XPB, XPD or XPG. Several of the protein (complex)es involved in NER participate in other DNA transactions as well. The XPF/ERCC1 complex probably has a dual involvement in a mitotic recombination pathway. All three NER genes associated with TTD are also implicated in basal transcription. This notion has important clinical implications. It is likely that the TTD symptoms not explained by a NER defect are caused by subtle insufficiencies in basal transcription. Thus TTD may represent a combined ‘repair/transcription syndrome’. To analyze the complex geno-phenotype relationship between mutations in NER genes and the clinical symptoms we have utilized gene targeting in mouse embryonal stem cells, to generate mouse mutants carrying defined genetic changes in various repair genes. The mouse models provide valuable tools for studying relationship between molecular defect and clinical symptoms, including cancer predisposition. All organisms have an evolved an intricate network of DNA repair systems, that permits elimination of virtually any type of DNA injury. Genetic defects in DNA repair pathways or in damage-induced cell cycle arrest result in genetic instability and a strong predisposition to cancer. Examples of this class of human syndromes are xeroderma pigmentosum (XP), Bloom's syndrome, Fanconi's anaemia, and ataxia telangiectasia. One of the major damage repair pathways is nucleotide excision repair (NER). This system. removes a broad spectrum of DNA lesions among which the mam UV-induced injury and bulky chemical adducts. Three NER-deficient human syndromes characterized by marked photosensitivity are known: XP, Cockayne syndrome (CS) and trichothiodystrophy (TTD). XP patients show pigmentation abnormalities and an over 1000 × increased risk of skin cancer caused by defects in one of at least 7 genes (XPA to XPG). CS displays sun sensitivity and overall developmental impairment. Two responsible genes are known: CSA and CSB. TTD is characterized by brittle hair, ichthyosis and many CS symptoms. The NER defect in TTD is due to mutations in TTDA, XPB or XPD. There are no indications for an increased risk of cancer in CS and TTD. Some patients show a combined XP + CS picture. They have been assigned to XPB, XPD or XPG. Several of the protein (complex)es involved in NER participate in other DNA transactions as well. The XPF/ERCC1 complex probably has a dual involvement in a mitotic recombination pathway. All three NER genes associated with TTD are also implicated in basal transcription. This notion has important clinical implications. It is likely that the TTD symptoms not explained by a NER defect are caused by subtle insufficiencies in basal transcription. Thus TTD may represent a combined ‘repair/transcription syndrome’. To analyze the complex geno-phenotype relationship between mutations in NER genes and the clinical symptoms we have utilized gene targeting in mouse embryonal stem cells, to generate mouse mutants carrying defined genetic changes in various repair genes. The mouse models provide valuable tools for studying relationship between molecular defect and clinical symptoms, including cancer predisposition.