Poly(ADP-ribose) polymerase 3 (PARP3) is the third member of the PARP family that catalyze a post-translational modification of proteins to promote, control or adjust numerous cellular events including genome integrity, transcription, differentiation, cell metabolism or cell death. In the late years, PARP3 has been specified for its primary functions in programmed and stressinduced double-strand break repair, chromosomal rearrangements, transcriptional regulation in the zebrafish and mitotic segregation. Still, deciphering the therapeutic value of its inhibition awaits additional investigations. In this review, we discuss the newest advancements on the specific functions of PARP3 in cancer aggressiveness exemplifying the relevance of its selective inhibition for cancer therapy.
Immunotoxins are emerging candidates for cancer therapeutics. These biomolecules consist of a cell targeting protein combined to a polypeptide toxin.Associations of both entities can be achieved either chemically by covalent bonds or genetically creating fusion proteins. However, chemical agents can affect activity and/or stability of the conjugate proteins and additional purification steps are often required to isolate the final conjugate from unwanted by-products. As for fusion proteins, they often suffer from low solubility and yield.In this report, we describe a straightforward conjugation process to generate an immunotoxin using co-associating peptides (named K3 and E3), originating from the tetramerization domain of p53. To that end, a nanobody targeting the human epidermal growth factor receptor 2 (nano-HER2) and a protein toxin fragment from Pseudomonas aeruginosa Exotoxin A (TOX) were genetically fused to the E3 and K3 peptides. Entities were produced separately in E. coli in soluble forms and at high yields. The nano-HER2 fused to the E3 or K3 helixes (nano-HER2-E3 and nano-HER2-K3) and the co-assembled immunotoxins (nano-HER2-K3E3-TOX and nano-HER2-E3K3-TOX) presented binding specificity on HER2 overexpressing cells with relative binding constants in the low nanomolar to picomolar range. Both toxin modules (E3-TOX and K3-TOX) and the combined immunotoxins exhibited similar cytotoxicity levels compared to the toxin alone (TOX). Finally, nano-HER2-K3E3-TOX and nano-HER2-E3K3-TOX evaluated on various breast cancer cells were highly potent and specific to kill HER2-overexpressing breast cancer cells with IC 50 values in the picomolar range. Altogether, we demonstrate that this non-covalent conjugation method using two co-assembling peptides can be easily implemented for modular engineering of immunotoxins targeting different types of cancers.
In breast cancer, Poly(ADP-ribose) polymerase 3 (PARP3) has been identified as a key driver of tumor aggressiveness exemplifying its selective inhibition as a promising surrogate for clinical activity onto difficult-to-treat cancers. Here we explored the role of PARP3 in the oncogenicity of glioblastoma, the most aggressive type of brain cancer. The absence of PARP3 did not alter cell proliferation nor the in vivo tumorigenic potential of glioblastoma cells. We identified a physical and functional interaction of PARP3 with the histone H3 lysine 9 methyltransferase G9a. We show that PARP3 helps to adjust G9a-dependent repression of the adhesion genes Nfasc and Parvb and the hypoxia-responsive genes Hif-2α, Runx3, Mlh1, Ndrg1, Ndrg2 and Ndrg4. Specifically for Nfasc, Parvb and Ndrg4, PARP3/G9a cooperate for an adjusted establishment of the repressive mark H3K9me2. While examining the functional consequence in cell response to hypoxia, we discovered that PARP3 acts to maintain the cytoskeletal microtubule stability. As a result, the absence of PARP3 markedly increases the sensitivity of glioblastoma cells to microtubule-destabilizing agents providing a new therapeutic avenue for PARP3 inhibition in brain cancer therapy.Poly(ADP-ribose) polymerase 3 (PARP3) is a member of the PARP family that catalyzes mono-ADP-ribosylation (or MARylation), the transfer of a single ADP-ribose molecule onto itself, a number of other protein substrates or on terminal phosphate residues at double-and single-strand break termini of DNA molecules 1-5 . PARP3 was originally identified as a key regulator of the classical non-homologous end-joining pathway (C-NHEJ) for the repair of double-strand breaks, and as an important protein securing telomeric segregation during mitosis 3-5 . Subsequently, PARP3 has been proposed to mediate the ADP-ribosylation of chromatin at sites of single strand breaks, to promote chromosomal rearrangements and limit G4 DNA and to stimulate breast tumor aggressiveness exemplifying its selective inhibition as a promising therapeutic strategy to treat highly aggressive cancers [6][7][8][9] . Accumulating studies also suggest emerging roles of PARP3 in the regulation of gene expression mediated by its interaction with chromatin regulators. In humans, PARP3 was reported to associate with several Polycomb group proteins (PcG) of the PRC2 complex namely EZH2, SUZ12, RbAp46/48, YY1 and HDAC1/2, key transcriptional regulators of embryogenesis and development 10 . In line with this, PARP3 was described to have pivotal functions in ectodermal specification and neural crest development in the Zebrafish by regulating the transcriptional expression of key transcription factors 11 . In glioblastoma cells, PARP3 was proposed to enhance the transcriptional activity of FOXM1 to confer glioblastoma cell radioresistance 12 .G9a (also known as EHMT2) and the closely related GLP1 (EHMT1) are SET-domain containing lysine methyltransferases that mono-(for GLP1) and di-methylate (for G9a) respectively histone 3 lysine 9 in euchromatin (H...
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