PARYLOME

pARylation-mediated regulation of cancer pathways

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 Obiettivo del progetto (Objective)

'Poly(ADP)ribosylation (pARylation) is an important post-translational modification of proteins that affects diverse biological processes such as DNA damage repair, apoptosis and transcription. The conjugation of Poly(ADP)-ribose (pADPr) to target proteins is mediated by members of the Poly(ADP)-ribose polymerase (ARTD/PARP) protein family. ADPr can be attached either as a single moiety or as chains forming poly-ADPr polymers (pADPr). The best-studied member of the ARTD/PARP family is ARTD1/PARP1, a DNA nick sensor enzyme that is activated following DNA damage. ARTD1/PARP1 is able to pARylate itself and a number of other protein targets, such as histones and DNA repair proteins, modulating their activity. Another member of this super-family is the telomeric ARTD/PARP, Tankyrase 1 (ARTD5/TNKS1), which plays an important role in maintaining telomere integrity, by pARylating its telomere partner, TRF1. Since the discovery that defects in homologous recombination sensitise cancer cells to PARP inhibitors there has been a renewed interest in ARTD/PARPs as attractive therapeutic targets. Furthermore, similarly to kinases and phosphorylation it seems likely that ARTD/PARPs and pARylation will have significant roles in the controls of a diverse range of cellular mechanisms. Using a combined approach of RNA interference (RNAi), drug treatment and mass spectrometry-based proteomic analysis, I propose to identify and characterise novel mono- and poly-(ADP)ribosylation targets, specific to particular ARTD/PARPs. This will help to resolve how (ADP)r conjugation regulates biological processes and contributes to the survival and maintenance of cancer cells. Moreover, using pathway specific reporter cell lines I will address the specific contribution of mAR/pARylated proteins for the regulation of several cancer-related signalling pathways. Ultimately, these studies will reveal novel and promising pARylation-based therapeutic targets for cancer treatment.'

Introduzione (Teaser)

Recent research has heralded poly adenosine diphosphate ribose polymerase (PARP) inhibitors as a potent weapon against cancer. EU research has investigated the biochemistry involved when these molecules are targeted in tumour cells.

Descrizione progetto (Article)

Mutations in BRCA1 and BRCA2 genes predispose women to breast and ovary cancer. In 2005, researchers discovered that inhibitors of the DNA repair process, PARP inhibitors, could target tumour cells with BRCA1 and BRCA2 mutations. In addition to PARP1 and PARP2, another member of the PARP superfamily, PARP5/Tankyrase is in the forefront as a therapeutic agent.

The EU-funded 'PARylation-mediated regulation of cancer pathways' (PARYLOME) project searched for additional targets of the PARP superfamily of enzymes to enhance understanding of PARP biology.

To identify new PARylated proteins, the researchers used genomic and proteomic-based techniques including immunoaffinity purification of key binding proteins followed by quantitative mass spectrometry. The result is a proteomic map of PARylation targets, the PARylome.

Once PARylated, some proteins become subject to degradation by a protein complex known as the proteasome. But many other outcomes may be induced by PARylation, such as cell signalling. Using PARP1/2 and Tankyrase specific inhibitors new targets for these proteins could be identified. And by integrating the PARylome data with a list of such proteins, the scientists have highlighted new exciting PARylation targets and PARylation dependent cellular phenomena.

For the future, research can continue with study of other PARylated proteins highlighted by the work of PARYLOME. One in particular is Sjogren Syndrome/Scleroderma Autoantigen 1. Another avenue to pursue is determining how Tankyrase modulates the different pathways where this protein is involved.

Cancer is one of the leading causes of death worldwide. Research into PARP inhibitors promises to identify more therapeutic targets and elucidate the mechanisms behind their action. Extending into other areas, PARP biology can be applicable to other diseases such as fibrosis and asthma.