DNA Damage and Repair in Light-Sensitive Human Skin Disease
About: This article is published in Journal of Investigative Dermatology.The article was published on 1970-03-01 and is currently open access. It has received 180 citations till now. The article focuses on the topics: DNA damage & Human skin.
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719 citations
TL;DR: The analysis of the repair of damage to DNA in mammalian cells leads not only to a knowledge of which environmental agents are deleterious to living creatures, but also to an understanding of which reaction products in DNA are potentially carcinogenic and which tissues are the more sensitive.
Abstract: The analysis of the repair of damage to DNA in mammalian cells leads not only to a knowledge of which environmental agents are deleterious to living creatures, but also to an understanding of which reaction products in DNA are potentially carcinogenic and which tissues are the more sensitive.
475 citations
287 citations
TL;DR: The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes, and the differential diagnosis should include other causes of childhood poikiloderma, other rare genodermatoses with prominent telangiectasias, which also share some clinical features.
Abstract: Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects), and/or subtle (visible only by radiographic analysis). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The sensitivity of RTS cells to genotoxic agents exploiting cells with a known RECQL4 status is being elucidated and is aimed at optimizing the chemotherapeutic regimen for osteosarcoma.
281 citations
Cites background from "DNA Damage and Repair in Light-Sens..."
...These showed either decreased DNA repair [103,104] or a normal response [4,16,27,105]....
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TL;DR: The subjects are three patients with distinct symptoms of xeroderma pigmentosum in which the cultured fibroblasts are different from those usually found in this disease, and a minority of those cases which are clinically diagnosed as XP constitute a biochemically distinct condition.
239 citations
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TL;DR: Patients with xeroderma pigmentosum develop fatal skin cancers when exposed to sunlight, and so the failure of DNA repair in the skin must be related to carcinogenesis.
Abstract: Normal skin fibroblasts can repair ultraviolet radiation damage to DNA by inserting new bases into DNA in the form of small patches. Cells from patients with the hereditary disease xeroderma pigmentosum carry a mutation such that repair replication of DNA is either absent or much reduced in comparison to normal fibroblasts. Patients with xeroderma pigmentosum develop fatal skin cancers when exposed to sunlight, and so the failure of DNA repair in the skin must be related to carcinogenesis.
1,649 citations
TL;DR: A comprehensive study of the buoyant density of DNA as a function of composition has been made and the linear relation previously reported has been confirmed.
1,549 citations
TL;DR: Application of the methods described in this paper as a tool for quantitative study of normal mammalian cell growth, physiology, genetics, and biochemistry, and the response of cells to drugs, viruses, high energy radiation, and other agents have been indicated.
Abstract: Two methods for simple and rapid plating of single HeLa cells, human, carcinomatous cells, are described. These result in growth and formation of colonies from each single cell. One of these procedures uses irradiated, non-multiplying "feeder" cells to condition the medium. The second requires more gentle handling of the cells, but otherwise is virtually the same as that used in plating bacteria on semisolid, nutrient media. By extension of these methods, it is possible to isolate single mutant colonies and grow pure clonal stocks of animal cells. These genetically uniform strains are much more homogeneous in their behavior than the parental HeLa cell population. Growth curves obtained from developing colonies are highly reproducible. The most active mutant stocks so far isolated display a generation time of 18 to 20 hours. In pooled human serum HeLa cells assume a highly stretched, ameboid form, with marked motility; whereas growth of the same cells in a variety of non-human sera results in tightly packed, columnar, epithelial-like morphology. The two cell types possess volumes, nuclear cross-sections, plating efficiencies, and generation times which are identical within experimental error, but display widely different cross-sectional areas, suggesting that the basic change occurs in the cell surface. It is conceivable that this change may be related to that which enables the cells of a compact tumor to become invasive. Animal cells subjected to the standard trypsinization procedures which involve mechanical trauma and repeated washings in incomplete media leak large amounts of P and suffer impaired ability to reproduce as isolated cells. Application of the methods described in this paper as a tool for quantitative study of normal mammalian cell growth, physiology, genetics, and biochemistry, and the response of cells to drugs, viruses, high energy radiation, and other agents have been indicated.
1,040 citations
TL;DR: The onset of DNA synthesis is associated with thymine dimer removal, which is suggested to be one step in cell recovery in resistant strains of E. coli.
Abstract: The state of thymine dimers during the time in which resistant strains of Escherichia coli recover from uvinduced delays in DNA synthesis was investigated. Five strains of E. coli were labeled by growth in Mg medium containing tritiated thymidine. At various times after uv irradiation (200 ergs/ mm2 at 265 m μ ), 1 ml aliquots of cell suspension were centrifuged, trichloracetic acid (TCA) supernatants were removed, and samples were prepared for chromatographic and counting procedures. Photoreactivating illumination was provided by black-light lamps. The radiation dose used stopped DNA synthesis and virtually eliminated colony-formation in two of the five strains. In the other three strains DNA synthesis was inhibited for 60 minutes and colony formation yields were reduced to 0.1 to 10 percent. The dimers disappeared from the acid- soluble fraction of the cells and appeared in the oligonucleotides. In a sensitive strain the dimers remained in the insoluble phase and were photoreactivable. Thus, the onset of DNA synthesis is associated with thymine dimer removal, which is suggested to be one step in cell recovery.
953 citations