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Serine ADP-ribosylation depends on HPF1

ABSTRACT: We report that serine ADPr is strictly dependent on HPF1 (histone PARylation factor 1. Quantitative proteomics revealed that serine ADPr does not occur in cells lacking HPF1. We identified three endogenous serine ADPr sites are located on the PARP-1 automodification domain. Further identification of serine ADPr on hundreds of other targets indicates that serine ADPr is a widespread modification.

INSTRUMENT(S): Orbitrap Fusion ETD, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Juan Jose Bonfiglio

LAB HEAD: Ivan Matic

PROVIDER: PXD005627 | Pride | 2017-02-10

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	160216_FS1_U2OS_Endogenous_PARP1_Rep1_ETD.raw	Raw
	160218_FS1_U2OS_Endogenous_PARP1_Rep2_ETD.raw	Raw
	160318_FS1_U2OS_Endogenous_PARP1_Rep3_ETD.raw	Raw
	160324_FS1_U2OS_Endogenous_PARP1_Rep4_ETD.raw	Raw
	160324_FS1_U2OS_Endogenous_PARP1_Rep5_ETD.raw	Raw

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Publications

Serine ADP-Ribosylation Depends on HPF1.

Bonfiglio Juan José JJ Fontana Pietro P Zhang Qi Q Colby Thomas T Gibbs-Seymour Ian I Atanassov Ilian I Bartlett Edward E Zaja Roko R Ahel Ivan I Matic Ivan I

Molecular cell 20170209 5

ADP-ribosylation (ADPr) regulates important patho-physiological processes through its attachment to different amino acids in proteins. Recently, by precision mapping on all possible amino acid residues, we identified histone serine ADPr marks in the DNA damage response. However, the biochemical basis underlying this serine modification remained unknown. Here we report that serine ADPr is strictly dependent on histone PARylation factor 1 (HPF1), a recently identified regulator of PARP-1. Quantita ...[more]

PMID: 28190768

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An HPF1/PARP1-based chemical biology strategy for exploring ADP-ribosylation

Project description:Strategies for installing authentic ADP-ribosylation (ADPr) at desired positions are fundamental for creating the tools needed to explore this elusive PTM in essential cellular processes. Here we describe a phospho-guided chemoenzymatic approach based on the Ser-ADPr writer complex for rapid, scalable preparation of a panel of pure, precisely-modified peptides. Integrating this streamlined methodology with phage display technology, we have developed the first site-specific as well as broad-specificity antibodies to mono-ADPr. These recombinant antibodies have been selected and characterized using multiple ADP-ribosylated peptides and tested by immunoblotting and immunofluorescence for their ability to detect physiological ADPr events. By enabling mono-ADPr proteomics and poly-to-mono comparisons at the modification site level, we have revealed the prevalence of mono-ADPr upon DNA damage and illustrated its dependence on PARG and ARH3. These and future tools created on our versatile chemical biology/recombinant antibody platform have broad potential to elucidate ADPr signaling pathways in health and disease.

2020-11-17 | PXD020589 | Pride

Histone ADP Ribosylation - Serine is a new target residue for endogenous ADP-ribosylation on histones

Project description:ADPr sites on histones obtained from cells were directly identified. We have identified 12 unique ADPr sites in human osteosarcoma cells and report serine ADPr as a new type of histone mark that responds to DNA damage.

2016-12-22 | PXD005462 | Pride

Comprehensive ADP-ribosylome analysis identifies tyrosine as an ADP-ribose acceptor site

Project description:Despite recent mass spectrometry (MS)-based breakthroughs, comprehensive ADP-ribose (ADPr)-site identification and localization remain challenging. Here, we report the establishment of an unbiased, multistep ADP-ribosylome data analysis workflow that led to the identification of tyrosine as a novel ARTD1/PARP1 dependent in vivo ADPr-acceptor. MS analyses of in vitro ADP-ribosylated proteins confirmed tyrosine as an ADPr-acceptor amino acid in RPS3A (Y155) and HPF1 (Y238) and demonstrated that trans modification of RPS3A is dependent on HPF1. We provide an ADPr-site Localization Spectra Database (ADPr-LSD), which contains 288 high-quality ADPr-modified peptide spectra, to serve as ADPr spectral references for correct ADPr-site localizations.

2018-06-28 | PXD009948 | Pride

Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signaling

Project description:In the mammalian DNA damage response, ADP-ribosylation signaling is of crucial importance to mark sites of DNA damage as well as recruit and regulate repairs factors. Specifically, the PARP1:HPF1 complex recognizes damaged DNA and catalyzes the formation of serine-linked ADP-ribosylation marks (mono-Ser-ADPr), which are extended into ADP-ribose polymers (poly-Ser-ADPr) by PARP1 alone. Poly-Ser-ADPr is reversed by PARG, while the terminal mono-Ser-ADPr is removed by ARH3. Despite its significance and apparent evolutionary conservation, little is known about ADP-ribosylation signaling in non-mammalian Animalia. The presence of HPF1, but absence of ARH3, in some insect genomes, including Drosophila species, raises questions regarding the existence and reversal of serine-ADP-ribosylation in these species. Here we show by quantitative proteomics that Ser-ADPr is the major form of ADP-ribosylation in the DNA damage response of Drosophila melanogaster and is dependent on the Parp1:Hpf1 complex. Moreover, our structural and biochemical data reveal a new mechanism of mono-Ser-ADPr removal by Drosophila Parg.

2023-05-26 | PXD036512 | Pride

The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome (part 1)

Project description:Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, the target residues of PARP1-mediated ADP-ribosylation remain ambiguous. To explicate the ADP-ribosylation regulome, we analyze human cells depleted for key regulators of PARP1 activity, histone PARylation factor 1 (HPF1) and ADPribosylhydrolase 3 (ARH3). Using quantitative proteomics, we characterize 1,596 ADP-ribosylation sites, displaying up to 1000-fold regulation across the investigated knockout cells. We find that HPF1 and ARH3 inversely and homogenously regulate the serine ADP-ribosylome on a proteome-wide scale with consistent adherence to lysine-serine-motifs, suggesting that targeting is independent of HPF1 and ARH3. Notably, we do not detect an HPF1-dependent target residue switch from serine to glutamate/aspartate under the investigated conditions. Our data support the notion that serine ADP-ribosylation mainly exists as mono-ADP-ribosylation in cells, and reveal a remarkable degree of histone co-modification with serine ADP-ribosylation and other post-translational modifications.

2021-10-07 | PXD023835 | Pride

Systems-wide analysis of serine-ADP-ribosylation reveals widespread occurrence and site-specific overlap with phosphorylation - Part 1, ADP-ribosylation data.

Project description:ADP-ribosylation (ADPr) is a reversible posttranslational modification involved in a range of cellular processes. Here, we report system-wide identification of serine ADPr in human cells upon oxidative stress. High-resolution mass spectrometry and unrestricted data processing confirm that serine residues are the major target of ADPr in HeLa cells. Proteome-wide analysis identifies 3,090 serine ADPr sites, with 97% of acceptor sites modulating more than 2-fold upon oxidative stress, while treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib abrogates this induction. Serine ADPr predominantly targets nuclear proteins, while structural-predictive analyses reveal that serine ADPr preferentially targets disordered protein regions. The identified ADP-ribosylated serines significantly overlap with known phosphorylated serines, and large-scale phosphoproteomics analysis provides evidence for the site-specific crosstalk between serine ADPr and phosphorylation. Collectively, we demonstrate that serine ADPr is a widespread modification and a major nuclear signaling response to oxidative stress, with a regulatory scope comparable to other extensive posttranslational modifications - Part 1, ADP-ribosylation data.

2018-08-29 | PXD009208 | Pride

The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome (part 2)

2021-10-11 | PXD027504 | Pride

Proteomic characterization of the heart and skeletal muscle reveals widespread Arginine ADP-ribosylation by the ectopic ADP-ribosyltransferase ARTC1

Project description:ADP-ribosylation has thus far been studied on the proteomic level mainly in cell lines and in combination with genotoxic stress. The clostridium-like ADP-ribosyltransferases (i.e. ARTC) are GPI-anchored or secreted proteins that are expressed in a highly tissue specific manner. Transcriptomic data revealed that ARTC1 is expressed in skeletal muscle and heart tissue. Although ARTC1 is highly active in vitro, identification of ARTC1 targets in vivo and subsequent characterization of ARTC1-regulated cellular processes on the proteome level has been challenging and only a few ADP-ribosylated targets are known. Using a new MS-based workflow, we provide the thus far most extensive identification of endogenous ADP-ribosylomes with hundreds of ARTC1-ADP-ribosylated proteins in C2C12 myotubes and in skeletal muscle and heart tissues from wild type and newly generated ARTC1 knockout mice. These proteins are ADP-ribosylated on arginine residues and mainly located on the cell surface or in the extracellular space. They are associated with signal transduction, transmembrane transport and muscle function. Together we provide the first comprehensive systems-level analysis of endogenous ADP-ribosylation in two different muscle tissues revealing a widespread function of ARTC1 and its targets.

2018-08-17 | PXD008041 | Pride

A site-specific analysis of the ADP-Ribosylome unveils Homogeneous Serine ADP-Ribosylation across wild-type and BRCA-mutant Breast Cancer cell lines

Project description:ADP-ribosylation (ADPr) signaling plays a crucial role in the DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage – PARP1 – are used as targeted therapies against breast cancers with BRCA1/2 mutations. However, development of resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To better understand the role of ADPr in PARPi sensitivity, we used Liquid Chromatography-Mass Spectrometry (LC-MS) for systems level analysis of the ADP-ribosylome in six breast cancer cell lines with different PARPi sensitivities. We identified 1632 sites on 777 proteins, primarily on serine residues, with a high site overlap of DNA damage-related proteins across all cell lines, demonstrating high conservation in ADPr signaling after DNA damage. We furthermore observed site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants, and unique ADPr sites in PARPi-resistant BRCA mutant cells, which we notably show to have low PARG levels and longer PARP1 ADPr chains.

2024-08-02 | PXD047613 | Pride

Preservation of Ester-linked Modifications Reveals Glutamate/Aspartate mono-ADP-ribosylation by PARP1 and its Reversal by PARG

Project description:Ester-linked post-translational modifications, including serine and threonine ubiquitination, have gained recognition as important cellular signals. However, their detection remains a significant challenge due to the chemical lability of the ester bond. This is the case even for long-known modifications, such as ADP-ribosylation on aspartate and glutamate, whose role in PARP1 signaling has recently been questioned. We have developed easily implementable methods for preserving ester-linked modifications, which, when combined with a specific and sensitive modular antibody and mass spectrometry, has enabled us to uncover DNA damage-induced aspartate/glutamate mono-ADP-ribosylation. This previously elusive signal represents an initial wave of PARP1 signaling, contrasting with the more enduring nature of serine mono-ADP-ribosylation. Unexpectedly, we have discovered that the poly-ADP-ribose hydrolase PARG is capable of reversing ester-linked mono-ADP-ribosylation in cells. Our methodology enables broad investigations of various ADP-ribosylation writers and, as illustrated here for noncanonical ubiquitination, it paves the way for exploring other emerging ester-linked modifications.

2024-05-08 | PXD048274 | Pride

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