Chaperones and their role in the cellular and clinical variability of Nijmegen Breakage Syndrome

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Nijmegen Breakage Syndrome is a rare DNA-Repair deficiency in which immunodeficiency and predisposition to cancer are the life threatening symptoms. The gene underlying the disorder, NBN, is involved in the repair of DNA double-strand breaks which are caused, amongst others, by ionising radiation (IR). In the proposal presented here, we will analyse chaperones within the context of NBS pathophysiology. Chaperones are essential in the stabilisation of proteins under stress and our previous work suggests that variation in the expression of chaperones may have a fundamental impact on the clinical course of the disease. In Nbn null-mutant mice, the expression of several chaperones, such as HSP60 and GRP58, was increased after irradiation in vivo in comparison to control mice. A further chaperone, ERp29, behaved differently. This protein was upregulated after irradiation only in the control mice; in the Nbn null-mutant mice the protein was not induced. This suggests that nibrin, the Nbn gene product, is required for upregulation of ERp29. In the project presented here, the mechanism of NBN-dependent ERp29 induction will be examined in detail. Furthermore, the role of the chaperones as modifying factors in the clinical course of the disease in NBS patients will be addressed. After induction of DNA damage by IR in a large collection of NBS cell lines the expression and activity of chaperones will be examined and correlated with the known cellular properties and, indeed, clinical course of the respective patients. In parallel, our collection of over 100 DNA samples from NBS patients will be examined for polymorphisms in the chaperone genes. These data can then also be correlated with the clinical data of the patients.