PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress

Schleicher, Emily M.; Galvan, Adri M.; Imamura‐Kawasawa, Yuka; Moldovan, George‐Lucian; Nicolae, Claudia M.

doi:10.1093/nar/gky658

Cited by 67 publications

(71 citation statements)

References 30 publications

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“…PARP-10 is an attractive therapeutic target in cancer, since it regulates cell proliferation through multiple mechanisms, including the regulation of ß-catenin, and relieving replication and oxidative stress [ 95 , 96 , 97 ]. Putt et al (2004) have described a fluorescent assay to measure the levels of PARP-10 activation by quantifying the levels of NAD + consumption [ 98 ].…”

Section: Development Of Mart Inhibitorsmentioning

confidence: 99%

MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Challa

Stokes

Kraus

2021

Cells

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Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation (PARylation) in cellular pathways, such as DNA repair and transcription, is well studied, the role of MARylation and MARTs (i.e., the PARP ‘monoenzymes’) are not well understood. Moreover, compared to PARPs, the development of MART-targeted therapeutics is in its infancy. Recent studies are beginning to shed light on the structural features, catalytic targets, and biological functions of MARTs. The development of new technologies to study MARTs have uncovered essential roles for these enzymes in the regulation of cellular processes, such as RNA metabolism, cellular transport, focal adhesion, and stress responses. These insights have increased our understanding of the biological functions of MARTs in cancers, neuronal development, and immune responses. Furthermore, several novel inhibitors of MARTs have been developed and are nearing clinical utility. In this review, we summarize the biological functions and molecular mechanisms of MARTs and MARylation, as well as recent advances in technology that have enabled detection and inhibition of their activity. We emphasize PARP-7, which is at the forefront of the MART subfamily with respect to understanding its biological roles and the development of therapeutically useful inhibitors. Collectively, the available studies reveal a growing understanding of the biochemistry, chemical biology, physiology, and pathology of MARTs.

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Section: Development Of Mart Inhibitorsmentioning

confidence: 99%

MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Challa

Stokes

Kraus

2021

Cells

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“…Still, ARTD10 ADP-ribosylates PLK1, significantly inhibiting its kinase activity and oncogenic function in hepatocellular carcinoma (HCC) [ 121 ]. ARTD10 interacts with and MARylates aurora A, inhibiting its kinase activity [ 136 , 137 ]. Moreover, ARTD10 promotes cellular proliferation and alleviates replication stress [ 136 ].…”

Section: Mono(adp-ribosyl) Transferases (Mart)mentioning

confidence: 99%

“…ARTD10 interacts with and MARylates aurora A, inhibiting its kinase activity [ 136 , 137 ]. Moreover, ARTD10 promotes cellular proliferation and alleviates replication stress [ 136 ]. Based on the chemical analysis of the reaction products, it was proposed that ARTD10 selectively modifies acidic amino acids.…”

Section: Mono(adp-ribosyl) Transferases (Mart)mentioning

confidence: 99%

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

Poltronieri

Celetti

Palazzo

2021

Cells

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Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.

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“…PARP12/ARTD12 in return appears to be capable of modifying non-structural viral proteins, indirectly leading to their ubiquitination and subsequent degradation, thereby limiting viral replication 11 . The anti-viral response is not the only function of MARylation, as MARylation by PARP10, for example, was reported to be involved in a wide range of processes, such as NF-κB signalling 12 , aurora kinase A and GSK3β activity 13,14 , mitochondrial function 15 and replication stress 16 . The recent development of MARylation detection reagents may assist further investigation of the physiological function of the modification [17][18][19] , which was not possible before due to lack of specific tools.…”

Section: The Posttranslational Modification Adp-ribosylation Is Involmentioning

confidence: 99%

Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome

Žaja

Aydin

Lippok

et al. 2020

Sci Rep

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The posttranslational modification ADP-ribosylation is involved in many cellular processes, with distinct roles for poly- and mono(ADP-ribosyl)ation (PAR- and MARylation, respectively). Reversibility of intracellular MARylation was demonstrated with the discovery of MACROD1, MACROD2 and TARG1, three macrodomain-containing enzymes capable of reversing MARylation of proteins and RNA. While the three enzymes have identical activities in vitro, their roles in cells are unclear and published data are partially contradictory, possibly due to a lack of validated reagents. We developed monoclonal antibodies to study these proteins and analysed their tissue distribution and intracellular localisation. MACROD1 is most prevalent in mitochondria of skeletal muscle, MACROD2 localises to nucleo- and cytoplasm and is found so far only in neuroblastoma cells, whereas the more ubiquitously expressed TARG1 is present in nucleoplasm, nucleolus and stress granules. Loss of MACROD1 or loss of TARG1 leads to disruption of mitochondrial or nucleolar morphology, respectively, hinting at their importance for these organelles. To start elucidating the underlying mechanisms, we have mapped their interactomes using BioID. The cellular localisation of interactors supports the mitochondrial, nucleolar and stress granule localisation of MACROD1 and TARG1, respectively. Gene ontology analysis suggests an involvement of MACROD1 and TARG1 in RNA metabolism in their respective compartments. The detailed description of the hydrolases’ expression, localisation and interactome presented here provides a solid basis for future work addressing their physiological function in more detail.

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PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress

Cited by 67 publications

References 30 publications

MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome

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