p53 in a Genetic Model: Illuminating Adaptive Radiation Responses

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Title: p53 in a Genetic Model: Illuminating Adaptive Radiation Responses
Author: Sogame, Naoko
Abstract: When cells are challenged by genotoxic stress , the tumor suppressor protein p53 promotes adaptive responses , including cell cycle arrest , DNA repair , or apoptosis . How these distinct fates are specified through an action of a single protein is not known . To study its functions in vivo we produced a targeted mutation at the Drosophila p53 (Dmp53 ) locus . I show that Dmp53 is required for damage -induced apoptosis but not for cell cycle arrest . Dmp53 function is also required for damage -induced transcription of two tightly linked cell death activators , reaper and sickle . When challenged by ionizing radiation , Dmp53 mutants exhibit radiosensitivity and genomic instability , indicating in our model , apoptosis is important for maintenance of genomic stability in response to ionizing radiation . I also examined a global transcriptional change in response to ionizing radiation in the absence of Dmp53 . Only 35 genes were constantly radiation responsive in wild type animals and Dmp53 was required for induction of a vast majority of the genes . The Radiation Induced p53 Dependent (RIPD ) genes include genes implicated in apoptosis and DNA repair as well as genes with unknown functions . The functional significance of RIPD genes for the activation of apoptosis was tested using RNAi . Thus far , I uncovered ribonucleotide reductase large subunit (RnrL ) as a novel Dmp53 target that is necessary for induction of caspase activation . Taken together , my study supports the notion that core ancestral functions of the p53 gene family are intimately coupled to cell death and possibly DNA repair as an adaptive response .
URI: http : / /hdl .handle .net /2152 .5 /405
Date: 2005-05-03

Citation

p53 in a Genetic Model: Illuminating Adaptive Radiation Responses. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /405 .

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