Molecular mechanisms of transcriptional regulation by Poly(ADP-ribose) polymerase 1

Kulaeva, Olga I.; Kotova, Elena; Chupyrkina, Anastasia A.; Nikitin, Dmitri; Kirpichnikov, Mikhaǐl P.; Studitsky, Vasily M.

doi:10.1134/s0026893315010094

Cited by 3 publications

(3 citation statements)

References 125 publications

(114 reference statements)

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“…Poly (ADP-ribose) polymerase-1 (PARP-1) is a widespread nuclear protein with a spectrum of different activities due to its DNA-binding and enzymatic properties [ 1 , 2 , 3 , 4 , 5 ]. PARP-1 uses β-NAD+ as a substrate to synthesize branched polymers of ADP-ribose (PAR) and to covalently modifies more than 40 nuclear proteins and transcription factors, including PARP-1 itself.…”

Section: Introductionmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.

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Section: Introductionmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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“…We should note that the linker and core histones not only can interact non-covalently with PAR, but can also undergo covalent poly(ADP-ribosyl)ation upon PARP activation. PARP-1 and PARP-2 were shown to modify the C- and N-termini of histones H1 and H2B, respectively, causing chromatin relaxation and facilitating the recruitment of repair proteins to the damage site [ 100 , 101 , 102 , 103 ].…”

Section: Principles Of Par Code Functioningmentioning

confidence: 99%

Poly(ADP-Ribosyl) Code Functions

et al. 2021

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Poly(ADP-ribosyl)ation plays a key role in cellular metabolism. Covalent poly(ADP-ribosyl)ation affects the activity of the proteins engaged in DNA repair, chromatin structure regulation, gene expression, RNA processing, ribosome biogenesis, and protein translation. Non-covalent PAR-dependent interactions are involved in the various types of cellular response to stress and viral infection, such as inflammation, hormonal signaling, and the immune response. The review discusses how structurally different poly(ADP-ribose) (PAR) molecules composed of identical monomers can differentially participate in various cellular processes acting as the so-called PAR code. The article describes the ability of PAR polymers to form functional biomolecular clusters through a phase-separation in response to various signals. This phase-separation contributes to rapid spatial segregation of biochemical processes and effective recruitment of the necessary components. The cellular PAR level is tightly controlled by a network of regulatory proteins: PAR code writers, readers, and erasers. Impaired PAR metabolism is associated with the development of pathological processes causing oncological, cardiovascular, and neurodegenerative diseases. Pharmacological correction of the PAR level may represent a new approach to the treatment of various diseases.

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“…According to these authors, discovery of compounds capable of preventing PARP1 involvement in the transcription process may lead to the development of a new class of drugs with higher specificity and less severe side effects. More information about the role of PARP1 in transcriptional regulation can be found in [ 97 - 101 ]. The use of a transcriptional system, which was previously obtained by these authors, in mononucleosome and polynucleosome systems enables the discovery and verification of transcriptional inhibitors of PARP1.…”

Section: Application Issues Of Existing Parp1 Inhibitors and Prospectmentioning

confidence: 99%

PARP1 Inhibitors: Antitumor Drug Design

et al. 2015

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The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1–2 million molecules per cell) serving as a “sensor” for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed.

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Molecular mechanisms of transcriptional regulation by Poly(ADP-ribose) polymerase 1

Cited by 3 publications

References 125 publications

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Poly(ADP-Ribosyl) Code Functions

PARP1 Inhibitors: Antitumor Drug Design

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