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HXMS on PARP1+DNA+HPF1 to study the dynamics of PARP1

ABSTRACT: The project is about studying the dynamics of PARP1 when bound to DNA and HPF1.

INSTRUMENT(S): Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ramya Billur

LAB HEAD: Dr. Ben E Black

PROVIDER: PXD026580 | Pride | 2022-02-17

REPOSITORIES: Pride

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HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications.

Langelier Marie-France MF Billur Ramya R Sverzhinsky Aleksandr A Black Ben E BE Pascal John M JM

Nature communications 20211118 1

PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multipl ...[more]

PMID: 34795260

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Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks

Project description:The project is about studying the dynamics of PARP1 when bound to DNA and veliparib derivatives.

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PARP1 proximity proteomics reveals interaction partners at stressed replication forks

Project description:PARP1 mediates poly-ADP-ribosylation of proteins on chromatin in response to different types of DNA lesions. PARP inhibitors are used for the treatment of BRCA1/2-deficient breast, ovarian, and prostate cancer. Loss of DNA replication fork protection is proposed as one mechanism that contributes to the vulnerability of BRCA1/2-deficient cells to PARP inhibitors. However, the mechanisms that regulate PARP1 activity at stressed replication forks remain poorly understood. Here, we performed proximity proteomics of PARP1 and isolation of proteins on stressed replication forks to map putative PARP1 regulators. We identified TPX2 as a direct PARP1-binding protein that regulates the auto-ADP-ribosylation activity of PARP1. TPX2 interacts with DNA damage response proteins and promotes homology-directed repair of DNA double-strand breaks. Moreover, TPX2 mRNA levels are increased in BRCA1/2-mutated breast and prostate cancers, and high TPX2 expression levels correlate with the sensitivity of cancer cells to PARP-trapping inhibitors. We propose that TPX2 confers a mitosis-independent function in the cellular response to replication stress by interacting with PARP1.

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PARP1 and Salmonella

Project description:BACKGROUND & AIMS: The immune system comprises an innate and an adaptive immune response to combat pathogenic agents. The human enteropathogen Salmonella enterica serovar Typhimurium invades the intestinal mucosa and triggers an early innate pro-inflammatory host gene response, which results in diarrheal disease. Several host factors are involved in the acute early response to Salmonella infection. Transcription factors and transcription co-regulators have an especially important function, because they are required for the expression and synthesis of pro-inflammatory cytokines, chemokines and adhesion molecules. A central transcription factor involved in inflammation is NF-ÎºB, which requires the nuclear protein PARP1 as co-factor for the expression of some of its target genes. Here, we investigated the role of PARP1 during Salmonella infection using a mouse model for Salmonella-induced colitis. METHODS: To study enterocolitis by Salmonella Typhimurium, an established mouse model system, which relies on streptomycin-pretreatment prior to Salmonella infection, was employed. Histopathologic signs of inflammation and cecum colonization at various time-points after infection of wild type and PARP1 knockout mice were analyzed. PARP1 expression in the gut mucosa was studied by quantitative RT-PCR, Western blot and immunofluorescence. Gene expression profiles of infected and control infected mice in the wild type or PARP1 knockout background were obtained by whole mouse genome arrays and confirmed by quantitative RT-PCR. 2 genotypes (wildtype, PARP1 knockout), 2 treatments (Salmonella SB300 infection, Salmonella SB161 control infection), 2 time-points (6h, 10h). 2-3 replicates/condition.

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

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.

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comparative mass spectrometry analysis of the PARP1 and PAR-PARP1 interactomes

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PARP1 expression drives the synergy between trabectedin and PARP1 inhibitors

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PARP1 expression predicts and determines synergy between PARP1 inhibitors and trabectedin.

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