Dissertation: Henok Kassahun - Molecular Biology

M.Sc. Henok Kassahun at the Biotechnology Centre in Oslo will defend his thesis for the Ph.D. grade (philosophiae doctor): Oxidative stress-response pathways maintain fitness of C. elegans DNA repair mutants

    Henok Kassahun

The importance of DNA repair is emphasized by a number of human neurodegenerative and age-related diseases being linked to defects in one of the repair processes. These complex diseases are associated with oxidative stress which induces oxidative DNA damage. Oxidative DNA damage is primarily repaired by the base excision repair (BER) pathway. However, the current knowledge of BER function in diseases prevention and progression remains rudimentary. There is little evidence to suggest that BER defects cause specific diseases associated with aging. This has been explained by partial redundancy between different glycosylases and overlap with other repair pathways. This study was motivated by our wish to understand how wild type phenotypes are maintained in mutants deficient in DNA glycosylases. C. elegans has only two DNA glycosylases, UNG-1 and NTH-1 and thus, enables us to circumvent the important limitation presented by extensive redundancy of DNA glycosylases in mammalian systems.

We have characterized mutants deficient for UNG-1 or NTH-1 but, contrary to our expectations, phenotypes in these mutants were comparable to the wild type animals. This suggests that extensive redundancy among DNA glycosylases is not a reason for the lack of phenotypes in DNA glycosylase-deficient mice. Global transcriptomic profiling and quantitative proteomic analysis and validation of these shows that mutants in DNA repair activate compensatory responses that involve in activation of oxidative stress responses which reflect a survival response. Moreover, we show that these responses are not due to accumulation of DNA damage in itself but rather active reprogramming that triggers a survival response to loss of DNA repair.

/klinmed/forskning/aktuelt/arrangementer/disputaser/2014/kassahun-henok.html

Published Dec. 17, 2015 8:42 AM