Serine is a new target residue for endogenous ADP-ribosylation on histones

Leidecker, Orsolya; Bonfiglio, Juán José; Colby, Thomas; Zhang, Qi; Atanassov, Ilian; Žaja, Roko; Palazzo, Luca; Stockum, Anna; Ahel, Ivan; Matić, Ivan

doi:10.1038/nchembio.2180

Cited by 210 publications

(319 citation statements)

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“…Additionally, determining the repertoire of targets of distinct PARPs and their sites of ADP-ribosylation in different tissues is in its infancy. Likewise, the broader spectrum of amino acids that function as acceptors of ADP-ribose is still being defined (e.g., serine and cysteine) (Leidecker et al 2016;Westcott et al 2017). Such information would provide new insights into the biological roles of PARP across tissues and in disease states.…”

Section: Discussionmentioning

confidence: 99%

“…Palazzo et al (2015) detected only two distinct sites of ADP-ribosylation on PARP-1, but these sites overlapped those identified by Daniels et al (2015b). HsNudT16 has also been used to identify serine residues on histones as novel acceptors of ADP-ribosylation (Leidecker et al 2016). While the use of NUDIX enzymes has some advantages, these enzymes appear to have an inherent bias for features of the peptide to which the ADP-ribose is attached.…”

Section: Chemical Cleavagementioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Chemical Cleavagementioning

confidence: 99%

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

2017

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“…Recently, a number of mass spectrometry-based proteomic approaches have been developed toward the analysis of protein PARylation. These studies have greatly facilitated the site-specific characterization of this PTM on several residues, including Asp, Glu, Lys, Arg and Ser (Bilan et al, 2017, Daniels et al, 2014, Leidecker et al, 2016, Martello et al, 2016, Zhang et al, 2013). However, these previous studies of protein ADP-ribosylation have generally examined only a few cell lines or tissues.…”

Section: Introductionmentioning

confidence: 99%

A Cell-Line-Specific Atlas of PARP-Mediated Protein Asp/Glu-ADP-Ribosylation in Breast Cancer

Zhen

Zhang

2017

Cell Reports

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Summary PARP1 plays a critical role in regulating many biological processes linked to cellular stress responses. Although DNA strand breaks are potent stimuli of PARP1 enzymatic activity, the context-dependent mechanism regulating PARP1 activation and signaling is poorly understood. We performed global characterization of the PARP1-dependent, Asp/Glu-ADP-ribosylated proteome in a panel of cell lines originating from benign breast epithelial cells, as well as common subtypes of breast cancer. From these analyses, we identified 503 specific ADP-ribosylation sites on 322 proteins. Despite similar expression levels, PARP1 is differentially activated in these cell lines under genotoxic conditions, which generates signaling outputs with substantial heterogeneity. By comparing protein abundances and ADP-ribosylation levels, we could dissect cell-specific PARP1 targets that are driven by unique expression patterns vs. cell-specific regulatory mechanisms of PARylation. Intriguingly, PARP1 modifies many proteins in a cell-specific manner, including those involved in transcriptional regulation, mRNA metabolism, and protein translation.

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“…It is essential here to apply a modified lysis protocol to the sample preparation that uses diluted sulfuric acid at a low temperature to prevent both degradation of ADPr and unwanted postlysis non-enzymatic ADP-ribosylation. This method, also jointly developed by the groups of Ahel and Matic, was immediately applied to histones, which are the canonical targets of ADP-ribosylation, and allowed the discovery of ADPr-Ser as the novel site of attachment to PAR (Leidecker et al, 2016). Significantly, no other ADPr-sites were detected in vivo, which immediately invites the audacious idea that serine is the true native site of ADP-ribosylation, suggesting that the other ADPr-amino acids are merely an in vitro artifact.…”

mentioning

confidence: 98%

“…In a recent issue of Molecular Cell, an important joint paper by the Ahel and Matic groups (Bonfiglio et al, 2017) reports on the prevalence of ADP-ribosylation at serine and, by doing so, brings a sense of normality to the ADP-ribosylation field. Methodologically, the work capitalizes on a clever mass-spectrometry-based proteomics approach that uses partial trypsin digestion of proteins (partial FASP) combined with a mild MS-MS fragmentation technique (electron-transfer dissociation [ETD]) (Leidecker et al, 2016). It is essential here to apply a modified lysis protocol to the sample preparation that uses diluted sulfuric acid at a low temperature to prevent both degradation of ADPr and unwanted postlysis non-enzymatic ADP-ribosylation.…”

mentioning

confidence: 99%