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Computational analysis of data from a genome-wide screening identifies new PARP1 functional interactors as potential therapeutic targets.

ABSTRACT: Knowledge of interaction network between different proteins can be a useful tool in cancer therapy. To develop new therapeutic treatments, understanding how these proteins contribute to dysregulated cellular pathways is an important task. PARP1 inhibitors are drugs used in cancer therapy, in particular where DNA repair is defective. It is crucial to find new candidate interactors of PARP1 as new therapeutic targets in order to increase efficacy of PARP1 inhibitors and expand their clinical utility. By a yeast-based genome wide screening, we previously discovered 90 candidate deletion genes that suppress growth-inhibition phenotype conferred by PARP1 in yeast. Here, we performed an integrated and computational analysis to deeply study these genes. First, we identified which pathways these genes are involved in and putative relations with PARP1 through g:Profiler. Then, we studied mutation pattern and their relation to cancer by interrogating COSMIC and DisGeNET database; finally, we evaluated expression and alteration in several cancers with cBioPortal, and the interaction network with GeneMANIA. We identified 12 genes belonging to PARP1-related pathways. We decided to further validate RIT1, INCENP and PSTA1 in MCF7 breast cancer cells. We found that RIT1 and INCENP affected PARylation and PARP1 protein level more significantly in PARP1 inhibited cells. Furthermore, downregulation of RIT1, INCENP and PSAT1 affected olaparib sensitivity of MCF7 cells. Our study identified candidate genes that could have an effect on PARP inhibition therapy. Moreover, we also confirm that yeast-based screenings could be very helpful to identify novel potential therapy factors.

SUBMITTER: Lodovichi S

PROVIDER: S-EPMC6505629 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Computational analysis of data from a genome-wide screening identifies new <i>PARP1</i> functional interactors as potential therapeutic targets.

Lodovichi Samuele S Mercatanti Alberto A Cervelli Tiziana T Galli Alvaro A

Oncotarget 20190412 28

Knowledge of interaction network between different proteins can be a useful tool in cancer therapy. To develop new therapeutic treatments, understanding how these proteins contribute to dysregulated cellular pathways is an important task. PARP1 inhibitors are drugs used in cancer therapy, in particular where DNA repair is defective. It is crucial to find new candidate interactors of PARP1 as new therapeutic targets in order to increase efficacy of PARP1 inhibitors and expand their clinical utili ...[more]

PMID: 31105872

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Project description:Microbe-Associated Molecular Patterns and virulence effectors are recognized by plants as a first step to mount a defence response against potential pathogens. This recognition involves a large family of extracellular membrane receptors and other immune proteins located in different sub-cellular compartments. We have used phage-display technology to express and select for Arabidopsis proteins able to bind bacterial pathogens. To rapidly identify microbe-bound phage, we developed a monitoring method based on microarrays. This combined strategy allowed for a genome-wide screening of plant proteins involved in pathogen perception. Two phage libraries for high-throughput selection were constructed from cDNA of plants infected with Pseudomonas aeruginosa PA14, or from combined samples of the virulent isolate DC3000 of Pseudomonas syringae pv. tomato and its avirulent variant avrRpt2. These three pathosystems represent different degrees in the specificity of plant-microbe interactions. Libraries cover up to 2 × 10(7) different plant transcripts that can be displayed as functional proteins on the surface of T7 bacteriophage. A number of these were selected in a bio-panning assay for binding to Pseudomonas cells. Among the selected clones we isolated the ethylene response factor ATERF-1, which was able to bind the three bacterial strains in competition assays. ATERF-1 was rapidly exported from the nucleus upon infiltration of either alive or heat-killed Pseudomonas. Moreover, aterf-1 mutants exhibited enhanced susceptibility to infection. These findings suggest that ATERF-1 contains a microbe-recognition domain with a role in plant defence. To identify other putative pathogen-binding proteins on a genome-wide scale, the copy number of selected-vs.-total clones was compared by hybridizing phage cDNAs with Arabidopsis microarrays. Microarray analysis revealed a set of 472 candidates with significant fold change. Within this set defence-related genes, including well-known targets of bacterial effectors, are over-represented. Other genes non-previously related to defence can be associated through this study with general or strain-specific recognition of Pseudomonas.

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Computational analysis of data from a genome-wide screening identifies new PARP1 functional interactors as potential therapeutic targets.

Publications

Computational analysis of data from a genome-wide screening identifies new <i>PARP1</i> functional interactors as potential therapeutic targets.

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