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      Human DNA repair diseases: From genome instability to cancer

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      Brazilian Journal of Genetics
      Sociedade Brasileira de Genética

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          Abstract

          Several human genetic syndromes have long been recognized to be defective in DNA repair mechanisms. This was first discovered by Cleaver (1968), who showed that cells from patients with xeroderma pigmentosum (XP) were defective for the ability to remove ultraviolet (UV)-induced lesions from their genome. Since then, new discoveries have promoted DNA repair studies to one of the most exciting areas of molecular biology. The present work intends to give a brief summary of the main known human genetic diseases related to DNA repair and how they may be linked to acquired diseases such as cancer

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          A single ataxia telangiectasia gene with a product similar to PI-3 kinase.

          A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.
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            The Bloom's syndrome gene product is homologous to RecQ helicases.

            The Bloom's syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.
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              A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia.

              Cell cycle checkpoints can enhance cell survival and limit mutagenic events following DNA damage. Primary murine fibroblasts became deficient in a G1 checkpoint activated by ionizing radiation (IR) when both wild-type p53 alleles were disrupted. In addition, cells from patients with the radiosensitive, cancer-prone disease ataxia-telangiectasia (AT) lacked the IR-induced increase in p53 protein levels seen in normal cells. Finally, IR induction of the human GADD45 gene, an induction that is also defective in AT cells, was dependent on wild-type p53 function. Wild-type but not mutant p53 bound strongly to a conserved element in the GADD45 gene, and a p53-containing nuclear factor, which bound this element, was detected in extracts from irradiated cells. Thus, we identified three participants (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.
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                Author and article information

                Journal
                bjg
                Brazilian Journal of Genetics
                Braz. J. Genet.
                Sociedade Brasileira de Genética (Ribeirão Preto, SP, Brazil )
                0100-8455
                1678-4502
                December 1997
                : 20
                : 4
                Affiliations
                [01] orgnameUniversidade Federal de Minas Gerais orgdiv1 Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas
                [02] orgnameUniversidade de São Paulo orgdiv1 Departamento de Microbiologia, Instituto de Ciências Biomédicas
                Article
                S0100-84551997000400032 S0100-8455(97)02000432
                10.1590/S0100-84551997000400032
                159f5cad-9469-4ae3-bd52-763ca59d0baa

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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                Figures: 0, Tables: 0, Equations: 0, References: 39, Pages: 0
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                SciELO Brazil

                Categories
                Human and medical genetics

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