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

Samuele Lodovichi,Tiziana Cervelli,Alberto Mercatanti,Alvaro Galli

doi:10.18632/oncotarget.26812

Samuele Lodovichi, Tiziana Cervelli + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.26812

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Journal: Oncotarget	Publication Date: Apr 12, 2019
Citations: 10	License type: cc-by

Affiliation: Istituto di Fisiologia Clinica, University of Pisa

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.

Highlights

Gene network analysis may reveal protein’s interaction with functional and therapeutic significance that could lead to development of new therapeutic treatment with higher clinical utility
We found 90 gene deletions able to suppress the poly (ADP-ribose) polymerase 1 (PARP1)-induced lethality in yeast; this indicates that these genes are somehow involved in PARP1 activity [31]
No additional INCENP interactor was found; interestingly, results obtained for RIT1 strengthened interaction to PARP1, since NTRK1 has been identified as a common member in their network (Figure 2C, right)

Summary

Introduction

Gene network analysis may reveal protein’s interaction with functional and therapeutic significance that could lead to development of new therapeutic treatment with higher clinical utility. We focused on the poly (ADP-ribose) polymerase 1 (PARP1) gene and its interaction network, because PARP1 inhibition is widely used in cancer therapy. Knowledge of its interactions could help to discover new applications of these inhibitors in different cancers with specific dysregulated pathways related to PARP1. PARP1 encodes for a nuclear protein that attaches a poly(ADP-ribose) polymer (PAR) to itself and other target proteins dealing with DNA repair and related pathways; PARylation is necessary to activate www.oncotarget.com. The prompt turnover of PAR is crucial for efficient DNA repair. Defects in PAR catabolism result in DNA damage that is deleterious to cells [6, 7]. Considering that cells are continuously exposed to various types of DNA-damage agents, DNA repair mechanisms must be robust and almost free of errors to ensure cell survival [8]

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