Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases

Rosenthal, Florian; Feijs, Karla L. H.; Frugier, Emilie; Bonalli, Mario; Forst, Alexandra; Imhof, Ralph; Winkler, Hans Christian; Fischer, David; Caflisch, Amedeo; Hassa, Paul O.; Lüscher, Bernhard; Hottiger, Michael O.

doi:10.1038/nsmb.2521

Cited by 286 publications

(387 citation statements)

References 51 publications

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“…1, C and D), indicating that, at least for murine innate cells, PARP12 is a genuine interferon stimulated gene or ISG. Finally, the capacity of PARP12 to express ADP-ribose transferase catalytic activity was confirmed using a series of in vitro assays using [ 32 P]NAD and a recombinant form of the Af1521 protein from the archaebacteria Archaeoglobus fulgidus, possessing an ADP-ribose recognizing module (termed macro domain) know to bind to both free and protein-bound mono and poly-ADP-ribose moieties (29,30) (Fig. 2).…”

Section: Parp12 Is An Interferon-stimulated Gene (Isg) Coding For Amentioning

confidence: 99%

PARP12, an Interferon-stimulated Gene Involved in the Control of Protein Translation and Inflammation

Welsby

Hutin

Gueydan

et al. 2014

Journal of Biological Chemistry

101

115

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Background:The individual role of members of the poly(ADP-ribose) polymerase family is unclear. Results: PARP12 displays a dual subcellular localization and effector function, controlling both protein translation and NF-B signaling. Conclusion: PARP12 mediates two important effector mechanisms linked to the establishment of an anti-viral state. Significance: ADP-ribosylation may play an important role in the innate control of microbial infections.

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Section: Parp12 Is An Interferon-stimulated Gene (Isg) Coding For Amentioning

confidence: 99%

PARP12, an Interferon-stimulated Gene Involved in the Control of Protein Translation and Inflammation

Welsby

Hutin

Gueydan

et al. 2014

Journal of Biological Chemistry

101

115

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“…Given MACROD2's recently described function in ADP ribosylation (20), and the fact that ER coactivators can have both estrogen dependent and independent mechanisms of mediating tumor growth (27) we sought to examine a broader array of Fig. 2.…”

Section: Macrod2 Overexpression Alters Protein Expression Of Er and Nmentioning

confidence: 99%

“…Studies have demonstrated that MACROD2 deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (19). More recent work demonstrates that MACRO domain containing proteins are involved with mono-ADP ribosylation, and can regulate cell signaling pathways and modify proteins involved with gene transcription (20). Interestingly, MACROD1 (LRP16) has been implicated in modulating ER and androgen receptor (AR) signaling in prior studies (21,22).…”

mentioning

confidence: 99%

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Mohseni

Cidado

Croessmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy.breast cancer | tamoxifen | resistance | MACROD2 | ER positive T he selective estrogen receptor modulator (SERM) tamoxifen is a highly effective drug for the prevention and treatment of estrogen receptor-alpha (ER) positive breast cancers (1). However, resistance to this drug remains a clinically important problem. The molecular mediators of tamoxifen resistance have not been fully elucidated. In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10, 11), and more recently, acquired somatic mutations and alterations in ER (12-17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.In this study we describe a previously unidentified gene, MACROD2, which is amplified and overexpressed in a subset of breast cancers. MACROD2 belongs to a family of genes containing a macro domain, an evolutionarily conserved protein motif (18), whose functional role until recently has been unclear. Studies have demonstrated that MACROD2 deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (19). More recent work demonstrates that MACRO domain containing proteins are involved with mono-ADP ribosylation, and can regulate cell signaling pathways and modify proteins involved with gene transcription (20). Interestingly, MACROD1 (LRP16) has been implicated in modulating ER and androgen receptor (AR) signaling in prio...

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“…This indicates that the catalytic activity of ARTD10 is required to recruit GAPDH, but it is not required to induce the formation of these cell bodies. Indeed, as also previously demonstrated [23], catalytically inactive ARTD10 can form these cell bodies. Moreover, their formation is not inhibited by pharmacological inhibition of the catalytic activity of ARTD10, as neither FK866 nor PJ34 affects the formation of these cell bodies.…”

Section: Discussionmentioning

confidence: 59%

ARTD10/PARP10 Induces ADP-Ribosylation of GAPDH and Recruits GAPDH into Cytosolic Membrane-Free Cell Bodies When Overexpressed in Mammalian Cells

et al. 2018

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Protein ADP-ribosylation is a reversible post-translational modification of cellular proteins that is catalysed by enzymes that transfer one (mono) or several (poly) units of ADP-ribose from β-NAD + to a specific amino acid of the target protein. The most studied member of the ADP-ribosyltransferase family is PARP1 (also known as ADP-ribosyltransferase diphtheria toxin-like 1, ARTD1), which is directly activated by DNA strand breaks and is involved in DNA damage repair, chromatin remodelling and transcriptional regulation. Much less is known about the further 16 members of this family. Among these, ARTD10/PARP10 has been previously characterised as a mono-ADP-ribosyltransferase with a role in cell proliferation and in NF-kB signalling. In the present study, we identified the glycolytic enzyme GAPDH as an interactor and a novel cellular target for ARTD10/PARP10. Moreover, we detected the co-localisation of GAPDH and ARTD10/PARP10 in well-defined cytosolic bodies, which we show here to be membrane-free, rounded structures using immunogold labelling and electron microscopy. Using the cognitive binding module macro domain to visualise ADP-ribosylated proteins by immunofluorescence microscopy in cells over-expressing the ARTD10/PARP10 enzyme, we show that the staining of the ARTD10/PARP10-dependent cytosolic bodies was lost when the cells were treated with compounds that inhibit ARTD10/PARP10, either by directly inhibiting the enzyme or by reducing the cellular NAD + levels. In parallel, the same treatment affected the co-localisation of GAPDH and ARTD10/PARP10, as GAPDH disappeared from the cytosolic cell bodies, which indicates that its presence there depends on the catalytic activity of ARTD10/PARP10. In line with this, in cells over-expressing the ARTD10/PARP10 catalytic domain alone, which we show here to form stress granules, GAPDH was recruited into stress granules. These data identify ARTD10/PARP10 as the enzyme that modifies and recruits GAPDH into cytosolic structures.

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Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases

Cited by 286 publications

References 51 publications

PARP12, an Interferon-stimulated Gene Involved in the Control of Protein Translation and Inflammation

PARP12, an Interferon-stimulated Gene Involved in the Control of Protein Translation and Inflammation

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

ARTD10/PARP10 Induces ADP-Ribosylation of GAPDH and Recruits GAPDH into Cytosolic Membrane-Free Cell Bodies When Overexpressed in Mammalian Cells

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