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Emphasis was on the analysis of the molecular and cellular basis of human genetic syndromes characterized by genome instability, sensitivity to DNA damaging agents, cancer predisposition and premature ageing, such as Xeroderma pigmentosum (XP), Cockayne syndrome (CS), Trichothiodystrophy (TTD) and Progeria (PR)
The collaborative studies of 5 groups resulted in the determination of gentic complementation groups of Russian patients with DNA repair associated deficiencies. The radiosensitivity in terms of chromosome aberrations and sister chromatid exchanges in cell lines from these patients was assess as part of the characterization of the cell biological consequences of a DNA repair associated defect. For this purpose immortalized cell lines were generated.
Studies on the topology of DNA replication showed that so-called replication foci behave as big replicons, comparable in size to cytogenetic chromosome bands. The analysis of the localization of repair proteins after UV exposure in repair proficient and deficient cells revealed interesting differences. At the molecular level the project contributed to understnding the function of the repair proteins being defective in XP, CS and TTD patients. The defect in a particular complementation group of XP (XP-F) was elucidated and found ti be a damage-structure-specific DNA cutting enzyme as part of an incision complex together with the ERCC-1 protein. The precise mutations in DNA repair genes in patients with XP-B, D and CS-B were identified and related to the disease phenotype of the patients. In XP-B and D the mutagenic oattern was consistent with the site of the mutation determining the phenotype. In CS-B neither the site nor the nature of the mutation correlated with the severity of the clinical features. Mouse models were generated for several DNA repair deficiencies, including ERCC1, CSB and TTD mutants. Evidence was presented that ERCC1 mouse mutants provide interesting models for prepature ageing. In contrast to the human situation mouse CSB and TTD mutants were shown to be cancer prone. These mouse models present excellent tools for further studies of the genotype - phenotype relationships in terms of cancer predispodition, growth retardation, neurological abnormalities and ageing.
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