Objective
EVALUATION OF GENETIC RISKS FROM IONIZING RADIATION. DETERMINATION OF CELLULAR RADIOSENSITIVITY AND RELATION TO REPAIR.
Skin biopsies from patients with a clinical suspicion of a disease associated with mutagen hypersensitivity were gathered. Fibroblast cultures were established from 79 patients and characteristic biochemical or cytogenetical abnormalities were demonstrated for xeroderma pigmentosum (XP) (12 cases), ataxia telangiectasia (AT) (23 cases), trichothiodystrophy (1 case), the Nijmegen breakage syndrome (NBS) (1 case), Fanconi's anaemia (4 cases). Prenatal diagnostic tests using chorionic villi and/or amniotic fluid cells were performed in pregnancies at risk of xeroderma pigmentosum, AT and Cockayne's syndrome (total of 10 cases).
For a genetic survey by complementation analysis the collection of ionising radiation sensitive human mutant cells was further expanded (in collaboration with Dr R A Gatti, University of California, Los Angeles). Among 45 cell strains genetically characterised so far, 6 complementation groups were discriminated: 4 with AT 2 with NBS. 1 patient having the clinical signs of both syndromes was assigned to 1 of the NBS groups, indicating that the 2 disorders are closely related. In addition, 2 AT sibships were identified not showing the radioresistant deoxyribinucleic acid (DNA) replication that was considered typical of AT and NBS. On the basis of these results the localisation on human chromosome 11q22-23 could be established for the AT gene from complementation group AB. This is the first chromosomal assignment of a human inherited disease with hypersensitivity to radiation.
A permanent cell line (XP44RO(MEL)) was established from a metastatic melanoma from an XP group C (XP-C) patient. As far as we know this is the fist established line derived from an XP-tumour. The tumourigenic properties were related to an N-ras oncogene, activated in codon 61 by a thymine adenine or guanine transversion at a potential site for dimer formation. This cell line should prove useful for studying the mechanism of excision repair, and the relationship between the XP defect and carcinogenesis.
In collaboration with the Leiden group X-ray and ultraviolet (UV) light sensitive mutant cell lines were isolated from the Chinese hamster V79 and Chinese hamster ovary (CHO) 9 cell lines. Some of the X-ray sensitive cell lines isolated from the V79 cell line behaved like AT fibroblasts with respects to DNA synthesis inhibition after X-ray irradiation.
It is our main interest to try to unravel the molecular intricacies of the excision pathway in humans, its involvement in (the prevention of) carcinogenesis and the primary defect in xeroderma pigmentosum (XP). To that aim we have primarily concentrated on the isolation of genes controlling nucleotide excision. Excision repair cross complementing (ERCC-1) was the first of a series of such genes that we have isolated.
In addition to ERCC-1, we have isolated a large number of other DNA repair genes.
The basic assumption is that at least a number of genes involved in deoxyribonucleic acid (DNA) repair processes are strongly conserved in evolution. This was based on our initial observation that the human excision repair cross correlating (ERCC-1) and yeast RAD10 excision repair proteins display significant amino acid sequence homology. Further evidence, supporting this hypothesis came from the analysis of a number of other DNA repair genes. We have used this homology to clone human DNA repair genes (homologous to Yeast Rad 6, Rad 23 and others).
1. ISOLATION AND CHARACTERIZATION OF DNA REPAIR GENES IN MAMMALIAN CELLS.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- medical and health sciences clinical medicine oncology skin cancer melanoma
- natural sciences physical sciences nuclear physics
- medical and health sciences clinical medicine obstetrics
- natural sciences chemical sciences organic chemistry amines
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Coordinator
ROTTERDAM
Netherlands
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