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DNA repair processes in human cells
169 44 Cleaver, J.E., Laboratory of Radiobiology, University of California, San Francisco, Calif. 94143 (U.S.A.) D N A repair processes in human cells
Numerous human diseases exhibit alterations in the mechanism by which radiation and chemical mutagen damaged DNA is repaired. Investigation of these diseases, notably: xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Fanconi's anemia, Cockayne's syndrome, and progeria, has shown that human repair systems are complex interrelated systems with distinct features that contrast with prokaryotic repair systems because of the organized structure of eukaryotic nucleoprotein. Human repair systems consist of at least, (a) excision repair, which has several branches depending on whether damage is excised enzymatically as nucleotides, bases or cross-linked lesions, or excised hydrolytically, and repaired with large or small patches, (b) post-replication repair, which is a complex perturbation of semiconservative replication that only occurs during the first few hours after DNA is damaged and may be confined to those replicons active at the time of damage. Post-replication repair has caffeine sensitive and insensitive components and may involve exchanges of short (less than 1000 nucleotides) pieces of single stranded DNA and inducible enzymes, (c) photoreactivation, which is only demonstrable under very restricted experimental conditions, in vitro, and may be a secondary property of other repair systems in human cells. Another phenomenon in mammalian cells, sisterchromatid exchanges, SCEs, consists of the exchange of large stretches of double-stranded DNA and is stimulated by unexcised damage in DNA, but this does not appear to involve any of the well-characterized DNA-repair processes because current models do not contain double~trand exchanges. XP contains at least 6 complementation groups (A, B, C, D, E and variant) and is defective predominantly in nucleotide excision repair but to some extent also in baseexcision repair, post-replication repair and photoreactivation. AT contains at least 3 complementation groups in which some are defective in excision repair of certain uncharacterized X-ray-induced damage. Fanconi's anemia appears defective in repairing cross-linked damage, especially when viewed at the chromosomal level. Cockayne's syndrome may have a defect in excision repair later in the pathway than XP, but the association of this syndrome with the sole representative of XP group B makes the status of both uncertain. A variety of other conditions have been associated with purported repair defects including progeria, chronic actinic keratosis, lupus erythematosis, pigmented xerodermoid, and chronic lymphocytic leukemia, but the status of many of these associations are obscure and some may be spurious. Work supported by the U.S. Energy Research and Development Administration.
45 Clive, D., Genetic Toxicology Laboratory, Burroughs WeUcome Co., Research Triangle Park, N.C. (U.S.A.)
Numerous human diseases exhibit alterations in the mechanism by which radiation and chemical mutagen damaged DNA is repaired. Investigation of these diseases, notably: xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Fanconi's anemia, Cockayne's syndrome, and progeria, has shown that human repair systems are complex interrelated systems with distinct features that contrast with prokaryotic repair systems because of the organized structure of eukaryotic nucleoprotein. Human repair systems consist of at least, (a) excision repair, which has several branches depending on whether damage is excised enzymatically as nucleotides, bases or cross-linked lesions, or excised hydrolytically, and repaired with large or small patches, (b) post-replication repair, which is a complex perturbation of semiconservative replication that only occurs during the first few hours after DNA is damaged and may be confined to those replicons active at the time of damage. Post-replication repair has caffeine sensitive and insensitive components and may involve exchanges of short (less than 1000 nucleotides) pieces of single stranded DNA and inducible enzymes, (c) photoreactivation, which is only demonstrable under very restricted experimental conditions, in vitro, and may be a secondary property of other repair systems in human cells. Another phenomenon in mammalian cells, sisterchromatid exchanges, SCEs, consists of the exchange of large stretches of double-stranded DNA and is stimulated by unexcised damage in DNA, but this does not appear to involve any of the well-characterized DNA-repair processes because current models do not contain double~trand exchanges. XP contains at least 6 complementation groups (A, B, C, D, E and variant) and is defective predominantly in nucleotide excision repair but to some extent also in baseexcision repair, post-replication repair and photoreactivation. AT contains at least 3 complementation groups in which some are defective in excision repair of certain uncharacterized X-ray-induced damage. Fanconi's anemia appears defective in repairing cross-linked damage, especially when viewed at the chromosomal level. Cockayne's syndrome may have a defect in excision repair later in the pathway than XP, but the association of this syndrome with the sole representative of XP group B makes the status of both uncertain. A variety of other conditions have been associated with purported repair defects including progeria, chronic actinic keratosis, lupus erythematosis, pigmented xerodermoid, and chronic lymphocytic leukemia, but the status of many of these associations are obscure and some may be spurious. Work supported by the U.S. Energy Research and Development Administration.
45 Clive, D., Genetic Toxicology Laboratory, Burroughs WeUcome Co., Research Triangle Park, N.C. (U.S.A.)