Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins

Alemasova, Elizaveta E.; Lavrik, Olga I.

doi:10.1093/nar/gkz120

Cited by 353 publications

(271 citation statements)

References 123 publications

(305 reference statements)

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“…PARP proteins exert their function through their physical association with or by the PARylation of partner proteins [3]. Although most of the immunomodulatory roles of PARP proteins have been based on studies of mice with the genetic deletion of these proteins (Table 1), PARP inhibitors might induce similar immune cell alterations that will modify their interaction with tumor cells.…”

Section: Parp Inhibitors As Immunomodulatory Agentsmentioning

confidence: 99%

“…Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are two enzymes of the PARP family of proteins that, in response to DNA damage, catalytically cleave β-NAD + and transfer ADP-ribose moieties onto specific amino residues of acceptor proteins. This process, termed poly(ADP-ribosyl)ation (PARylation), forms poly(ADP-ribose) (PAR) polymers varying in size and branching, which have diverse functional and structural effects on target proteins [1][2][3]. The deletion of either PARP-1 or PARP-2 in mice is associated with disturbances of DNA integrity and repair, supporting key shared functions of these proteins that are pivotal to DNA repair [4].…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which posttranslationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.

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Section: Parp Inhibitors As Immunomodulatory Agentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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“…The potential energies were calculated in order to determine the highly probable interaction regions by using scoring techniques as a result of the docking process. Alemasova and Lavrik's review shows the NAD-binding site of PARP1 [29]; however there is no simulation for NAD-bound PARP2 and PARP4.…”

Section: Resultsmentioning

confidence: 99%

Investigation of the three-dimensional structure and interaction mechanism of poly (ADP-ribose) polymerase 4

Ünlü

Dinç

2020

Biotechnology & Biotechnological Equipment

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Poly ADP-ribose polymerases (PARPs) are family of proteins that use nicotinamide adenine dinucleotide (NAD) as substrate. Seventeen putative PARP sequences were determined in the human genome. Although PARPs show a variety of functions and low sequence identities, they share common structural and functional properties. In our study, PARP1 and PARP2 and PARP4 sequences in different species were compared; it was found that active sites of PARP1 for human, rat and mouse have highly conserved sequence. Overall folding of PARP1, PARP2 and PARP4 confirms similarity in catalytic domains but can differ in substrate proteins. The threedimensional structure of PARP4 was interacted with NAD using the molecular docking method and the interaction sites were determined. When we modeled the three-dimensional structure of PARP4 using MODELLER v9.22 algorithm and examined the interaction with Autodock v4.2 in computer environment, we observed that the enzyme is connected with a common motif similar to PARP1 and PARP2. When PARP1 and PARP2 interact with this common motif with NAD, we experimentally observed that these structures interact directly with NAD in order to undergo catalytic reactions by Thermal-Shift assay. The PARP4-NAD complex with the binding energy À26.73 kJ/mol was further used for molecular dynamics analysis. Root mean square deviation (RMSD) for all backbone atoms, electrostatic energy, van der Waals energy of PARP4-NAD complex were studied in the form of molecular dynamics trajectories to throw light on the medically important PARP family of enzymes. ARTICLE HISTORY

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“…In the human genome, 18 PARP family members have been identified thus far. Among them, PARP1 is a founding member of this family, well-known for its essential function in DNA damage repair and other cellular processes, such as chromatin remodeling, transcription and cell death signaling [2,6,7]. In fact, the term "PARP family" is misleading, because, besides PARP1, only PARP2 and PARP3 as well as PARP4 and PARP5 (tankyrases 1 and 2) have been shown to harbor PARylating activity, although the nature of PAR generated by these enzymes is different [3,8].…”

Section: Introductionmentioning

confidence: 99%

“…For example, which of the described functions are related to the PARP1 protein itself and which are attributed to its enzymatic product PAR [2]? Several recent reviews have comprehensively described the PARP family [7,12,13] and also summarized development of PARP inhibitors in clinical applications [11,14,15]. Hence, this review will concentrate on an overview of biochemical and biological studies of PARP1, aiming to illustrate the contribution of PARP1 protein and its enzymatic product PAR, as well as PAR interactors in biological processes in vivo.…”

mentioning

confidence: 99%

The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers

Kamaletdinova

Fanaei-Kahrani

Wang

2019

Cells

111

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Poly(ADP-ribosyl)ation (PARylation) is catalysed by poly(ADP-ribose) polymerases (PARPs, also known as ARTDs) and then rapidly removed by degrading enzymes. Poly(ADP-ribose) (PAR) is produced from PARylation and provides a delicate and spatiotemporal interaction scaffold for numerous target proteins. The PARylation system, consisting of PAR synthesizers and erasers and PAR itself and readers, plays diverse roles in the DNA damage response (DDR), DNA repair, transcription, replication, chromatin remodeling, metabolism, and cell death. Despite great efforts by scientists in biochemistry, cell and molecular biology, genetics, and pharmacology over the last five decades, the biology of PARPs and PARylation remains enigmatic. In this review, we summarize the current understanding of the biological function of PARP1 (ARTD1), the founding member of the PARP family, focusing on the inter-dependent or -independent nature of different functional domains of the PARP1 protein. We also discuss the readers of PAR, whose function may transduce signals and coordinate the cellular processes, which has recently emerged as a new research avenue for PARP biology. We aim to provide some perspective on how future research might disentangle the biology of PARylation by dissecting the structural and functional relationship of PARP1, a major effector of the PARPs family.

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Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins

Cited by 353 publications

References 123 publications

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Investigation of the three-dimensional structure and interaction mechanism of poly (ADP-ribose) polymerase 4

The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers

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