Proteomics

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Temporal modulation of the NF-kB network in response to different types of DNA damage ETOPOSIDE C4PR_LIV


ABSTRACT: Different types of DNA damage can initiate phosphorylation-mediated signalling cascades that result in stimulus specific pro- or anti-apoptotic cellular responses. Amongst its many roles, the NF-κB transcription factor RelA is central to the DNA damage response pathway. Yet, understanding of the co-ordinated signalling mechanisms that result in these different DNA damaging agents inducing specific cellular outcomes through RelA remains unclear. Here, we examine the temporal effects of exposure of U2OS cells to either etoposide (ETO) or hydroxyurea (HU) on the phosphorylation status of RelA and its protein binding partners, using label-free quantitative phosphoproteomics. Although there were relatively few stimulus specific differences overall in the phosphorylated RelA interactome in response to either DNA damaging agent, we observed subtle, but significant changes in the phosphorylation states of the RelA bound proteins as a function of both the type of and duration of the DNA damaging agent used. The DNA double strand break (DSB) inducing ETO invoked more rapid, sustained responses than HU, with regulated targets primarily involved in transcription, cell division and (unsurprisingly) DSB repair. Kinase substrate prediction of confident, differentially regulated phosphosites suggests possible roles for CDK1 and MAPK3/ERK1 signaling, in addition to the known roles of ATM/ATR. In contrast, HU-induced replicative stress mediated more temporally dynamic regulation, with phosphoprotein components of the RelA network having known roles in rRNA/mRNA processing and translational initiation, many of which contained a 14-3-3ε binding motif. Our data thus point to differential regulation of key cellular processes and the involvement of unique signalling pathways in modulating DNA damage-specific functions of RelA.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Catarina Franco  

LAB HEAD: Claire Eyers

PROVIDER: PXD019587 | Pride | 2021-09-09

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
CF_TiO2_enrich_120MIN_1-01.msf Msf
CF_TiO2_enrich_120MIN_1.msf Msf
CF_TiO2_enrich_120MIN_1.raw Raw
CF_TiO2_enrich_120MIN_2.msf Msf
CF_TiO2_enrich_120MIN_2.raw Raw
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Publications

Temporal modulation of the NF-κB RelA network in response to different types of DNA damage.

Campbell Amy E AE   Ferraz Franco Catarina C   Su Ling-I LI   Corbin Emma K EK   Perkins Simon S   Kalyuzhnyy Anton A   Jones Andrew R AR   Brownridge Philip J PJ   Perkins Neil D ND   Eyers Claire E CE  

The Biochemical journal 20210201 3


Different types of DNA damage can initiate phosphorylation-mediated signalling cascades that result in stimulus specific pro- or anti-apoptotic cellular responses. Amongst its many roles, the NF-κB transcription factor RelA is central to these DNA damage response pathways. However, we still lack understanding of the co-ordinated signalling mechanisms that permit different DNA damaging agents to induce distinct cellular outcomes through RelA. Here, we use label-free quantitative phosphoproteomics  ...[more]

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