Role of PARP-1 in DNA damage induced NF-kappaB-dependent gene expression View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2008-2011

FUNDING AMOUNT

675000 CHF

ABSTRACT

a) BackgroundIn eukaryotes, DNA damage was described to alter the global pattern of gene expression, which orchestrates a variety of cellular events. Although the transcription factor Nuclear factor kappa B (NF-kappaB) is mainly associated with its pivotal role in immune and inflammatory responses, it has been known for a long time that NF-kappaB is also induced by ‘‘non-inflammatory’’ endogenous stimuli such as genotoxic stress. Indeed, DNA damage-induced NF-kappaB activation controls the transcription of cell survival genes, allowing cells to escape the otherwise lethal effect of DNA damage and to initiate pathways of DNA repair. Despite this notable physiological relevance, little details are known about the molecular requirements enabling NF-kappaB-dependent gene expression initiated upon DNA damage. The nature of the genotoxic-stress-induced signaling cascade appears to depend strongly on the genotoxic stimulus and on the cell type, giving rise to many discrepancies in the literature and hindering the emergence of a general model.Own studies and those from others have recently provided evidence that poly(ADP-ribose)polymerase 1 (PARP-1) cannot only function as DNA damage sensor, but also as a general transcriptional co-activator. PARP-1 has been reported to increase the transcriptional activity of different transcription factors.b) Working hypothesisOur preliminary experiments reveal that NF-kappaB-dependent gene expression is severely impaired in PARP-1 knockout cells treated with etoposide, a genotoxic compound described to induce DNA double-strand breaks. Based on these experiments and on the observation that the enzymatic activity of PARP-1 is strongly enhanced upon DNA damage, we hypothesize that PARP-1 plays a role in DNA damage induced NF-kappaB-dependent gene expression.c) Specific aimsThe aim of this research proposal is to further investigate the functional relevance of PARP-1 in DNA damage induced NF-kappaB-dependent gene expression. The grant proposal will mainly address four different aspects: (i) We will investigate the role of PARP-1 in DNA damage induced nuclear translocation of NF-kappaB (role of PARP-1 as sensor/inducer).(ii) We will elaborate the role of PARP-1 as transcriptional co-activator in DNA damage induced NF-kappaB-dependent gene expression (role of PARP-1 as transcriptional co-activator).(iii) We will elucidate a possible contribution of the enzymatic activity of PARP-1 for NF-kappaB-dependent gene expression under DNA damaging conditions.(iv) Finally we will analyze the influence of the cell cycle on one or both of the above-mentioned roles of PARP-1 (i and ii).d) Experimental design/methodsStandard and recently developed molecular and cell biology techniques will be applied in this grant proposal. Since the cellular chromatin context is a very important parameter to be taken into consideration, primary cells isolated from mice (with different genetic background) as well as different transformed mouse and human cells will be included in these studies. All necessary facilities and expertise for these technologies are available in the laboratory.e) Expected value of the proposed projectThis grant proposal aims to elucidate the molecular interplay of DNA damage signaling and gene transcription with special focus on PARP-1 and NF-kappaB-dependent gene expression. Being able to manipulate the activation of NF-kappaB by genotoxic compounds that often accounts for the phenomenon of acquired chemo resistance impeding effective cancer therapy, is of great clinical relevance. More... »

URL

http://p3.snf.ch/project-122421

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