The role of poly(ADP-ribose) in the DNA damage signaling network

Malanga, Maria; Althaus, Felix R.

doi:10.1139/o05-038

Cited by 256 publications

(229 citation statements)

References 97 publications

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“…Therefore, application of PARP inhibitors may represent a double-edged sword, which on the one hand, promotes cell death by inhibiting DNA repair while on the other hand, via activation of PI-3K/Akt pathway, promotes cell survival. This dual effect of PARP inhibition could be responsible for the contradictory data in this field [43,44,45,46]. It also suggests that to utilize the cell death promoting effect of PARP-1 inhibition in cancer therapy, the activation of PI-3k-Akt pathway should be suppressed by specific inhibitors.…”

Section: Page 19 Of 44mentioning

confidence: 99%

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

Szántó

Hellebrand

Bognár

et al. 2009

Biochemical Pharmacology

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Running Title: PARP inhibition promotes Taxol resistance via Akt activationThe nonstandard abbreviations used are: PARP, Poly (ADP-ribose) polymerase; PAR, poly (ADP-ribose); PI-3K, phosphatidylinositol-3-kinase; Akt/PKB, protein kinase B; MTT + , 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance.Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinaseAkt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.

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Section: Page 19 Of 44mentioning

confidence: 99%

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

Szántó

Hellebrand

Bognár

et al. 2009

Biochemical Pharmacology

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“…While some ARTDs modify substrates by transferring iteratively multiple ADP-ribose units resulting in poly-ADP-ribosylation (PARylation), most ARTDs mono-ADP-ribosylate (MARylate) their substrates (Kleine et al, 2008). ARTDs function in DNA damage repair (Malanga and Althaus, 2005;Nicolae et al, 2014Nicolae et al, , 2015, the unfolded protein response (Jwa and Chang, 2012), apoptosis Koh et al, 2005), heat shock (Petesch and Lis, 2008), cellular signaling (Feijs et al, 2013a;, cell division (Chang et al, 2004(Chang et al, , 2005(Chang et al, , 2009Ha et al, 2012), as well as transcription and chromatin regulation Schreiber et al, 2006). PARylating ARTDs (pARTDs; ARTD1-6), most prominently ARTD1, have been the focus of cancer related research during the past two decades.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Venkannagari

Verheugd

Koivunen

et al. 2016

Cell Chemical Biology

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SUMMARYMembers of the human diphtheria toxin-likeADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.3

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“…The intervention of PARP1 and PARP2 takes place early in the steps of the DNA repair process, as these enzymes bind to and are activated by DNA nicks (Pleschke et al, 2000). Upon poly-ADP ribosylation, PARPs recruit to the damaged site components of BER and NER machineries (Schreiber et al, 2002;Malanga and Althaus, 2005). Therefore, inhibition of PARP activity would prevent recruitment of repair enzymes to DNA breaks, hampering strand rejoining and consequent generation of permanent single/double-strand breaks, which in turn triggers cell death.…”

Section: Introductionmentioning

confidence: 99%

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

108

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New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

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The role of poly(ADP-ribose) in the DNA damage signaling network

Cited by 256 publications

References 97 publications

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

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