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Modulators of DNA damage-induced cell death in Caenorhabditis elegans


Eberhard, Ralf. Modulators of DNA damage-induced cell death in Caenorhabditis elegans. 2012, University of Zurich, Faculty of Science.

Abstract

The formation and maintenance of tissues and organs mandate a fine-tuned balance between cell proliferation and cell loss. Apoptosis as one form of programmed cell death ascertains the timely and innocuous removal of superfluous, damaged, or potentially harmful cells. Disturbances leading to excessive or reduced apoptosis are at the basis of severe pathogenic processes like neurodegeneration or tumor growth. In my studies, I aimed at furthering our understanding of the genetically determined cell- death mechanism as well as its interactions with physiological or pathological tissue environments – knowledge that is needed for the elaboration of preventive or therapeutic strategies. Using the model organism Caenorhabditis elegans, I have characterised several novel determinants of the level of apoptotic death, particularly in response to DNA damage caused by ionizing irradiation. The key findings of this work: i) DNA-repair factors of homologous recombination (HR) are required for UV-C induced apoptosis. ii) unc-119 regulates cell death and removal. This gene has been widely used as a transgene marker and potentially confounds findings of apoptosis research in C. elegans. iii) RNA polymerase I (transcription of rRNA) and other factors of ribosome biosynthesis modulate DNA damage-induced and constitutive cell death. This is likely mediated by Ras/MAPK signalling, that has manifold well-known effects in growth and development. We show a novel role for this signalling pathway in irradiation-induced apoptosis. iv) Besides these genetic determinants, the food type – i.e. for the nematode different types of bacteria – can largely influence the number of irradiation-induced or physiologic cell corpses. Many of our observations suggest a central effector that modulates the level of constitutive as well as of exogenously provoked apoptosis. v) In addition to DNA damage response, the p53 homolog CEP-1 is involved in developmental apoptosis as well as in non-irradiation-induced germ cell death, which blurs the current genetic distinction between DNA damage-induced and physiological apoptosis. Conclusively, the high evolutionary conservation of the proteins and mechanisms studied here should allow to transfer our observations in the worm C. elegans to the biology of the healthy and diseased human.

Abstract

The formation and maintenance of tissues and organs mandate a fine-tuned balance between cell proliferation and cell loss. Apoptosis as one form of programmed cell death ascertains the timely and innocuous removal of superfluous, damaged, or potentially harmful cells. Disturbances leading to excessive or reduced apoptosis are at the basis of severe pathogenic processes like neurodegeneration or tumor growth. In my studies, I aimed at furthering our understanding of the genetically determined cell- death mechanism as well as its interactions with physiological or pathological tissue environments – knowledge that is needed for the elaboration of preventive or therapeutic strategies. Using the model organism Caenorhabditis elegans, I have characterised several novel determinants of the level of apoptotic death, particularly in response to DNA damage caused by ionizing irradiation. The key findings of this work: i) DNA-repair factors of homologous recombination (HR) are required for UV-C induced apoptosis. ii) unc-119 regulates cell death and removal. This gene has been widely used as a transgene marker and potentially confounds findings of apoptosis research in C. elegans. iii) RNA polymerase I (transcription of rRNA) and other factors of ribosome biosynthesis modulate DNA damage-induced and constitutive cell death. This is likely mediated by Ras/MAPK signalling, that has manifold well-known effects in growth and development. We show a novel role for this signalling pathway in irradiation-induced apoptosis. iv) Besides these genetic determinants, the food type – i.e. for the nematode different types of bacteria – can largely influence the number of irradiation-induced or physiologic cell corpses. Many of our observations suggest a central effector that modulates the level of constitutive as well as of exogenously provoked apoptosis. v) In addition to DNA damage response, the p53 homolog CEP-1 is involved in developmental apoptosis as well as in non-irradiation-induced germ cell death, which blurs the current genetic distinction between DNA damage-induced and physiological apoptosis. Conclusively, the high evolutionary conservation of the proteins and mechanisms studied here should allow to transfer our observations in the worm C. elegans to the biology of the healthy and diseased human.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Hengartner Michael O
Communities & Collections:UZH Dissertations
Dewey Decimal Classification:Unspecified
Language:English
Place of Publication:Zürich
Date:2012
Deposited On:16 Apr 2019 15:22
Last Modified:15 Apr 2021 15:01
Number of Pages:325
OA Status:Green

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