Translation-coupled sensing and degradation of RNA-protein crosslinks
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1002344 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22462570.fastq.gz | Fastqsanger.gz | |||
| SRR22462571.fastq.gz | Fastqsanger.gz | |||
| SRR22462572.fastq.gz | Fastqsanger.gz | |||
| SRR22462573.fastq.gz | Fastqsanger.gz | |||
| SRR22462574.fastq.gz | Fastqsanger.gz |
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Project description:Translation-coupled sensing and degradation of RNA-protein crosslinks [Ribo-Seq: dataset_2]
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Project description:Translation-coupled sensing and degradation of RNA-protein crosslinks [Ribo-Seq: dataset_1]
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Project description:Reactive aldehydes are abundant cytotoxic metabolites, which challenge homoeostasis by crosslinking cellular macromolecules. Aldehyde-induced DNA-DNA crosslinks cause cancer and bone marrow failure in Fanconi anemia, while covalent DNA-protein crosslinks require proteolytic repair to prevent liver tumours and premature ageing. Whether RNA damage contributes to the toxicity of aldehydes and whether cells possess mechanisms to resolve RNA-protein crosslinks (RPCs) in particular is unknown. Studying the specific consequences of aldehyde-induced RNA damage is challenging due to confounding induction of DNA damage. Here, we establish photoactivatable ribonucleosides as a tractable model system to study aldehyde-mimicking RNA damage in the absence of DNA damage. We find that RNA crosslinking damage causes translational stress by stalling elongating ribosomes, which causes cell death upon ZAKα-dependent activation of the ribotoxic stress response (RSR) and GCN2-dependent activation of the integrated stress response (ISR). Moreover, we discover the principles of a translation-coupled cellular quality control mechanism that targets RPCs. Collisions between translating ribosomes and crosslinked mRNA-binding proteins trigger their ubiquitylation and subsequent proteasomal degradation. Our findings reveal RNA damage and RPC formation as a central aspect of aldehyde-induced toxicity and establish a framework to study the cellular responses to these threats in mechanistic detail.
2023-11-13 | GSE240135 | GEO
Project description:Reactive aldehydes are abundant cytotoxic metabolites, which challenge homoeostasis by crosslinking cellular macromolecules. Aldehyde-induced DNA-DNA crosslinks cause cancer and bone marrow failure in Fanconi anemia, while covalent DNA-protein crosslinks require proteolytic repair to prevent liver tumours and premature ageing. Whether RNA damage contributes to the toxicity of aldehydes and whether cells possess mechanisms to resolve RNA-protein crosslinks (RPCs) in particular is unknown. Studying the specific consequences of aldehyde-induced RNA damage is challenging due to confounding induction of DNA damage. Here, we establish photoactivatable ribonucleosides as a tractable model system to study aldehyde-mimicking RNA damage in the absence of DNA damage. We find that RNA crosslinking damage causes translational stress by stalling elongating ribosomes, which causes cell death upon ZAKα-dependent activation of the ribotoxic stress response (RSR) and GCN2-dependent activation of the integrated stress response (ISR). Moreover, we discover the principles of a translation-coupled cellular quality control mechanism that targets RPCs. Collisions between translating ribosomes and crosslinked mRNA-binding proteins trigger their ubiquitylation and subsequent proteasomal degradation. Our findings reveal RNA damage and RPC formation as a central aspect of aldehyde-induced toxicity and establish a framework to study the cellular responses to these threats in mechanistic detail.
2023-11-13 | GSE219055 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-11-13 | GSE240136 | GEO
Project description:Reactive aldehydes are abundant cytotoxic metabolites, which challenge homoeostasis by crosslinking cellular macromolecules. Whether RNA damage contributes to the toxicity of aldehydes and whether cells possess mechanisms to resolve RNA-protein crosslinks (RPCs) in particular is unknown. Studying the specific consequences of aldehyde-induced RNA damage is challenging due to confounding induction of DNA damage. Here, we establish photoactivatable ribonucleosides as a tractable model system to study aldehyde-mimicking RNA damage in the absence of DNA damage. The aim of this phosphoproteome measurement is to elucidate the changes in phosphorylation sites upon RPC induction using the treatment with a photoactivatable-ribonucleoside-enhanced crosslinking (PAR-CL) by incubation with 4-thiouridine (4-SU) and subsequent crosslinking by UVA irradiation.
2023-11-13 | PXD038398 | Pride
Project description:The aim of the measurements was to investigate RNA damage and RNA-protein crosslinks (RPC) formation in the context of aldehyde-induced toxicity. For this, a photoactivatable-ribonucleoside-enhanced crosslinking (PAR-CL) strategy using 4-thiouridine (4-SU) and UVA-radiation was used. The submitted dataset contains data from LC-MS/MS measurements of crosslinks between proteins and poly-adenylated mRNAs (mRPCs). The measurements included the following six samples sets: Sample set 1 (9 runs = 3 conditions in 3 replicates): RPCs after formaldehyde (FA) and 4-SU + UVA treatment isolated using the protein-x-linked RNA extraction (XRNAX) protocol (doi:10.1016/j.cell.2018.11.004) Conditions: RPCs from untreated HAP1 =Ctrl RPCs from HAP1 treated with FA RPCs from HAP1 treated with 4-SU + UVA Sample set 2 (12 runs = 4 conditions in 3 replicates): mRPCs after 4-SU + UVA treatment using poly-A pulldown Conditions: mRPCs from untreated HAP1=Ctrl mRPCs from HAP1 treated with UVA but without 4-SU (0h after irradiation) mRPCs from HAP1 treated with 4-SU but without UVA mRPCs from HAP1 treated with 4-SU + UVA (0h after irradiation) Sample set 3 (24 runs = 6 conditions in 4 replicates): mRPCs after 4-SU + UVA and Ub-E1i treatment using poly-A pulldown Conditions: mRPCs from HAP1 treated with 4-SU + UVA (0h, 0.5h and 1h after irradiation) mRPCs from HAP1 treated with 4-SU + UVA and Ub-E1i (0h, 0.5h and 1h after irradiation) Sample set 4 (24 runs = 6 conditions in 4 replicates): mRPCs after 4-SU + UVA and MG132 treatment isolated using poly-A pulldown Conditions: mRPCs from HAP1 treated with 4-SU + UVA (0h, 0.5h and 1h after irradiation) mRPCs from HAP1 treated with 4-SU + UVA and MG132 (0h, 0.5h and 1h after irradiation) Sample set 5 (24 runs = 6 conditions in 4 replicates): mRPCs after 4-SU + UVA and ANS treatment using isolated poly-A pulldown Conditions: mRPCs from HAP1 treated with 4-SU + UVA (0h, 0.5h and 1h after irradiation) mRPCs from HAP1 treated with 4-SU + UVA and ANS (0h, 0.5h and 1h after irradiation) Sample set 6 (24 runs = 6 conditions in 4 replicates ): mRPCs after 4-SU+UVA in AAVS1 control and RNF14 KO cells using poly-A pulldown mRPCs from HAP1 AAVS1 control cells (clone #6) treated with 4-SU+UVA (0h, 0.5h and 1h after irradiation) mRPCs from HAP1 RNF15 KO cells (clone #15) treated with 4-SU+UVA (0h, 0.5h and 1h after irradiation) Abbreviations: 4-SU: 4-thiouridine ANS: Anisomycine, a translation elongation inhibitor FA: Formaldehyde MG132: proteasome-inhibitor mRPCs: crosslinks between proteins and poly-adenylated mRNAs isolated by Poly-A pulldown RPCs: crosslinks between proteins and RNA isolated by XRNAX Ub-E1i: ubiquitin E1 inhibitor (E1i, TAK-243) UVA: Ultraviolet A
2023-11-03 | PXD038332 | Pride
Project description:Coupled evolution of transcription and mRNA degradation.
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Project description:PxP-MS (Purification of x-linked Proteins coupled to Mass Spectrometry) was used to assess the role of CSB in DNA-protein crosslink repair. The CSB protein is a sensor that can detect stalled RNA polymerases at sites of DNA damage, thereby triggering transcription-coupled repair mechanisms. DPCs were induced in WT and CSB knock-out RPE1 cells using a pulse of formaldehyde. To identify crosslinked proteins that specifically require CSB for repair, DNA-protein crosslinks were isolated from cells using PxP either directly after formaldehyde exposure or following a chase in drug-free media and identified by mass spectrometry.
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