A novel role for the mono-ADP-ribosyltransferase PARP14/ARTD8 in promoting homologous recombination and protecting against replication stress

Nicolae, Claudia M.; Aho, Erin R.; Choe, Katherine N.; Constantin, Daniel; Hu, He Juan; Lee, Deokjae; Myung, Kyungjae; Moldovan, George‐Lucian

doi:10.1093/nar/gkv147

Cited by 57 publications

(58 citation statements)

References 55 publications

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“…Moreover, it has been described to repress the anti-proliferative and pro-apoptotic IFN/STAT1 axis in B-cell lymphoma [61]. PARP14 is involved in genomic stability [62]. Of note, genetic inhibition of PARP9 and PARP14 was shown to increase chemotherapy efficacy in prostate cancer cells [63].…”

Section: Discussionmentioning

confidence: 99%

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

Gaston

Cheradame

Yvonnet³

et al. 2016

Oncotarget

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Activation of the IFN/STAT1 pathway is closely associated with drug response and recurrence of breast cancer treated by chemotherapy. The aim of the current study was to elucidate the molecular mechanisms involved upstream and downstream of this pathway in order to identify distinct entities that might be manipulated to improve treatment efficacy. Four breast cancer cell lines (T-47D, MCF7, MDA-MB-231 and HBCx-19 established from the eponymous PDX) were treated in vitro with mafosfamide, a DNA damage inducer. In two of these cell lines (MCF7 and HBCx-19), genotoxic treatment upregulated type I IFN expression leading to paracrine activation of IFN/STAT1 signaling pathway after 6–8 days. We show that STING, a well-characterized inducer of IFN in immune cells, is rapidly triggered in MCF7 cells under genotoxic stress and forms nuclear foci that co-localize with phosphorylated IRF-3 and γH2AX. STING silencing abrogated chemotherapy-induced type I IFN production and signaling and potentiated genotoxic treatment efficacy as it promoted cell death extent and delayed cell colony regrowth. Similar results were obtained after silencing PARP12, one selected gene of the IFN/STAT1 pathway fingerprint. In summary, this study provides the first demonstration of STING activation in breast cancer cells. Our data suggest that genotoxic-induced, STING-mediated type I IFN signaling is a cell-intrinsic mechanism of breast cancer cell survival and regrowth.

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Section: Discussionmentioning

confidence: 99%

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

Gaston

Cheradame

Yvonnet³

et al. 2016

Oncotarget

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“…Notably, the identified mARTDs that show weak affinity to OUL35 are also suggested to be involved in cancer linked processes. ARTD8 plays a role in the survival of cancerous multiple myeloma cells (Barbarulo et al, 2013) and promotes DNA damage repair (Nicolae et al, 2015), while ARTD15 is a regulator of the unfolded protein response (Jwa and Chang, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…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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“…In addition, we identified proteins that were not previously identified as RNA-binding and likely represent a set of novel candidate RBPs. Interestingly, these include proteins with previous links to DNA repair such as RECQL4 (Singh et al 2010), PARP14 (Nicolae et al 2015), CHD4 (O'Shaughnessy and Hendrich 2013), and ASCC3 ( Fig. 1J; Dango et al 2011;Williamson et al 2017).…”

Section: Many Nucleolar Proteins Exhibit Increased Binding To Polyadementioning

confidence: 99%

DDX54 regulates transcriptome dynamics during DNA damage response

et al. 2017

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The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A) + RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by proteinprotein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.

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A novel role for the mono-ADP-ribosyltransferase PARP14/ARTD8 in promoting homologous recombination and protecting against replication stress

Cited by 57 publications

References 55 publications

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

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

DDX54 regulates transcriptome dynamics during DNA damage response

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