Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Barbarulo, Alessandro; Iansante, Valeria; Chaidos, Aristeidis; Naresh, Kikkeri N.; Rahemtulla, Amin; Franzoso, Guido; Karadimitris, Anastasios; Haskard, D. O.; Papa, Salvatore; Bubici, Concetta

doi:10.1038/onc.2012.448

Cited by 107 publications

(148 citation statements)

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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%

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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Section: Discussionmentioning

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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“…PARP-14 inhibits STAT1 phosphorylation and proinflammatory gene expression in IFNγ-stimulated macrophages while enhancing STAT6 phosphorylation and anti-inflammatory gene expression in IL-4-stimulated macrophages, in part by antagonizing the actions of PARP-9 and by ADP-ribosylating STAT1 (Iwata et al 2016). In multiple myeloma, a cancer of plasma cells, Jun N-terminal kinase 2 (JNK2) signals for cell survival through PARP-14, which binds to and inhibits JNK1 to promote the survival of myeloma cells and reduce their sensitization to anti-myeloma agents (Barbarulo et al 2013).…”

Section: Parp-14mentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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“…5C), indicating that BAL1 may directly stimulate JAK2-mediated phosphorylation of STAT1 and thereby promote the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1b. Remarkably, a recent study provided the first evidence that the BAL1-related BAL2/ARTD8 promotes the survival of myeloma cells by inhibiting the kinase activity of c-Jun N-terminal kinase 1 (JNK1) (Barbarulo et al, 2012). Since phosphorylation of STAT1a on S727 is not affected by BAL1, our results indicate that BAL1 influences the nuclear activities of the transcriptionally repressive isoform STAT1b thereby tipping HEK293 cells were co-transfected with expression vectors for HA-tagged BAL1 full length along with FLAG-tagged STAT1, STAT2, STAT3, STAT4, STAT5 or STAT6 and subsequently stimulated for 1 hour with 1000 U/ml IFNc.…”

Section: Bal1 Stimulates the Phosphorylation And Nuclear Translocatiomentioning

confidence: 99%

BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes in diffuse large B-cell lymphoma

Camicia

Bachmann

Winkler

et al. 2013

Journal of Cell Science

100

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SummaryThe B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFNc) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms, STAT1a and STAT1b, on Y701 and thereby promotes the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1b. Moreover, BAL1 physically interacts with both STAT1a and STAT1b through its macrodomains in an ADP-ribosylation-dependent manner. BAL1 directly inhibits, together with STAT1b, the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show for the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFNc-STAT1-IRF1-p53 axis and mediates proliferation, survival and chemoresistance in DLBCL. As a consequence constitutive IFNc-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL.

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Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Cited by 107 publications

References 50 publications

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

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

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes in diffuse large B-cell lymphoma

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