Orphan Macrodomain Protein (Human C6orf130) Is an O-Acyl-ADP-ribose Deacylase

Peterson, Francis C.; Chen, Fan; Lytle, Betsy L.; Rossi, Marianna Nicoletta; Ahel, Ivan; Denu, John M.; Volkman, Brian F.

doi:10.1074/jbc.m111.276238

Cited by 68 publications

(99 citation statements)

References 49 publications

(71 reference statements)

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“…For TARG1/C6orf130 protein also NMR solution structures for both apo and ADP-ribose-bound complex are available in the literature (31). Interestingly, in none of the 20 final NMR conformers from apo and 20 from the complexed protein phosphate binding loop reaches a position so far away from the binding cleft as in SCO6735 structure.…”

Section: Resultsmentioning

confidence: 99%

Disruption of Macrodomain Protein SCO6735 Increases Antibiotic Production in Streptomyces coelicolor

Lalić¹,

Marjanović²,

Palazzo

et al. 2016

Journal of Biological Chemistry

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ADP-ribosylation is a post-translational modification that can alter the physical and chemical properties of target proteins and that controls many important cellular processes. Macrodomains are evolutionarily conserved structural domains that bind ADP-ribose derivatives and are found in proteins with diverse cellular functions. Some proteins from the macrodomain family can hydrolyze ADP-ribosylated substrates and therefore reverse this post-translational modification. Bacteria and Streptomyces, in particular, are known to utilize protein ADP-ribosylation, yet very little is known about their enzymes that synthesize and remove this modification. We have determined the crystal structure and characterized, both biochemically and functionally, the macrodomain protein SCO6735 from Streptomyces coelicolor. This protein is a member of an uncharacterized subfamily of macrodomain proteins. Its crystal structure revealed a highly conserved macrodomain fold. We showed that SCO6735 possesses the ability to hydrolyze PARP-dependent protein ADP-ribosylation. Furthermore, we showed that expression of this protein is induced upon DNA damage and that deletion of this protein in S. coelicolor increases antibiotic production. Our results provide the first insights into the molecular basis of its action and impact on Streptomyces metabolism.

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Section: Resultsmentioning

confidence: 99%

Disruption of Macrodomain Protein SCO6735 Increases Antibiotic Production in Streptomyces coelicolor

Lalić¹,

Marjanović²,

Palazzo

et al. 2016

Journal of Biological Chemistry

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“…However, a note of caution should be raised in that the true significance of sirtuin activity inside the cells is still elusive. So are also the biological significance of the protein modifications that sirtuins perform and the interplay between sirtuins and other regulatory proteins, such as macrodomain proteins, that act in concert with them to regulate intracellular ADP-ribose levels [129, 130]. The answers to these questions will come with time and will help design rational applications of sirtuin-targeting agents in humans.…”

Section: Resultsmentioning

confidence: 99%

Rejuvenating Sirtuins: The Rise of a New Family of Cancer Drug Targets

Bruzzone

Parenti

Grozio

et al. 2013

CPD

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Sirtuins are a family of NAD+-dependent enzymes that was proposed to control organismal life span about a decade ago. While such role of sirtuins is now debated, mounting evidence involves these enzymes in numerous physiological processes and disease conditions, including metabolism, nutritional behavior, circadian rhythm, but also inflammation and cancer. SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have all been linked to carcinogenesis either as tumor suppressor or as cancer promoting proteins. Here, we review the biological rationale for the search of sirtuin inhibitors and activators for treating cancer and the experimental approaches to their identification.

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“…Macrodomains, typically composed of approximately 120 residues, have been shown to recognize more varied substrates and were shown to bind both PAR and different ADP-ribose metabolites, such as O-acetyl-ADP-ribose as well as mono(ADP-ribosyl)ated (MARylated) proteins Jankevicius et al, 2013;Karras et al, 2005;Kustatscher et al, 2005;Lambrecht et al, 2015). Interestingly, some macrodomains have also evolved enzymatic activity and are capable of processing such ADP-ribose metabolites (Barkauskaite et al, 2013b;Feijs et al, 2013;Jankevicius et al, 2013;Neuvonen and Ahola, 2009;Peterson et al, 2011;Rosenthal et al, 2013;Shull et al, 2005). Therefore, unsurprisingly, macrodomain-containing proteins have been implicated in a diverse set of cellular functions (Ahel et al, 2009;Krietsch et al, 2013;Pehrson and Fried, 1992;Timinszky et al, 2009).…”

Section: Protein Adp-ribosylationmentioning

confidence: 99%

“…Indeed, these proteins were shown not to act on the ADP-ribosyl moieties present on the lysine residues Rosenthal et al, 2013). It is worth mentioning that TARG1 and MacroD1/D2 can also hydrolyze a sirtuin-by-product O-acetyl-ADP-ribose, suggesting that MARHs can accommodate different acidic groups covalently linked to ADP-ribose Peterson et al, 2011).…”

Section: Macrod1/d2mentioning

confidence: 99%

Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation

2015

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The poly(ADP-ribose) polymerases (PARPs) are a major family of enzymes capable of modifying proteins by ADP-ribosylation. Due to the large size and diversity of this family, PARPs affect almost every aspect of cellular life and have fundamental roles in DNA repair, transcription, heat shock and cytoplasmic stress responses, cell division, protein degradation, and much more. In the past decade, our understanding of the PARP enzymatic mechanism and activation, as well as regulation of ADP-ribosylation signals by the readers and erasers of protein ADP-ribosylation, has been significantly advanced by the emergence of new structural data, reviewed herein, which allow for better understanding of the biological roles of this widespread post-translational modification.

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Orphan Macrodomain Protein (Human C6orf130) Is an O-Acyl-ADP-ribose Deacylase

Cited by 68 publications

References 49 publications

Disruption of Macrodomain Protein SCO6735 Increases Antibiotic Production in Streptomyces coelicolor

Disruption of Macrodomain Protein SCO6735 Increases Antibiotic Production in Streptomyces coelicolor

Rejuvenating Sirtuins: The Rise of a New Family of Cancer Drug Targets

Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation

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