Modeling of the Enzyme—Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1

Nilov, Dmitry K.; Pushkarev, Sergey V.; Gushchina, Irina V.; Manasaryan, Garri; Кирсанов, Кирилл И.; Švedas, Vytas K.

doi:10.1134/s0006297920010095

Cited by 11 publications

(6 citation statements)

References 67 publications

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“…PARP1 is an abundant nuclear enzyme (1-2 million molecules per cell) and a nucleosome-binding protein localized in cell nuclei and involved in a variety of cellular processes including DNA repair, chromatin organization and transcription [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Nucleosome Reorganization by PARP1

Nilov

Pushkarev

Kotova

et al. 2021

IJMS

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Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair, chromatin organization and transcription. During transcription initiation, PARP1 interacts with gene promoters where it binds to nucleosomes, replaces linker histone H1 and participates in gene regulation. However, the mechanisms of PARP1-nucleosome interaction remain unknown. Here, using spFRET microscopy, molecular dynamics and biochemical approaches we identified several different PARP1-nucleosome complexes and two types of PARP1 binding to mononucleosomes: at DNA ends and end-independent. Two or three molecules of PARP1 can bind to a nucleosome depending on the presence of linker DNA and can induce reorganization of the entire nucleosome that is independent of catalytic activity of PARP1. Nucleosome reorganization depends upon binding of PARP1 to nucleosomal DNA, likely near the binding site of linker histone H1. The data suggest that PARP1 can induce the formation of an alternative nucleosome state that is likely involved in gene regulation and DNA repair.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Nucleosome Reorganization by PARP1

Nilov

Pushkarev

Kotova

et al. 2021

IJMS

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“…Previous works on PARP‐1 MD simulations reported the involvement of polar interactions (hydrogen bonding and pi‐cation) and non‐polar interaction (Pi‐stacking) playing crucial roles in the higher activity of ligands in the active site of PARP‐1. Also, previous works described the involvement of van der Waals and hydrophobic interactions in the ligand‐PARP‐1 activities [11,17–19] . Findings from the current study may provide useful insights for the future rational design of novel PARP‐1 inhibitors for the treatment of cancer disease.…”

Section: Introductionmentioning

confidence: 59%

Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di‐Substituted Oxadiazole‐Based Dibenzo‐Azepine‐Dione Derivatives on Poly (ADP‐Ribose) Polymerase‐1

Okunlola

Soremekun

Olotu

et al. 2020

Chemistry & Biodiversity

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Numerous studies have established the involvement of Poly (ADP-ribose) Polymerase-1 (PARP-1) in cancer presenting it as an important therapeutic target over recent years. Although homology among the PARP protein family makes selective targeting difficult, two compounds [d11 (0.939 μM) and d21 (0.047 μM)] with disparate inhibitory potencies against PARP-1 were recently identified. In this study, free energy calculations and molecular simulations were used to decipher underlying mechanisms of differential PARP-1 inhibition exhibited by the two compounds. The thermodynamics calculation revealed that compound d21 had a relatively higher ΔG bind than d11. High involvement of van der Waal and electrostatic effects potentiated the affinity of d21 at PARP-1 active site. More so, incorporated methyl moiety in d11 accounted for steric hindrance which, in turn, prevented complementary interactions of key site residues such as TYR889, MET890, TYR896, TYR907. Conformational studies also revealed that d21 is more stabilized for interactions in the active site compared to d11. We believe that findings from this study would provide an important avenue for the development of selective PARP-1 inhibitors.

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“…Such a structural adjustment of PARP1 on a nucleosome can occur because of the topological features of nucleosomal DNA, such as helix bending and closely spaced DNA gyres, as well as the interaction of PARP1 with histones, in particular, with tails of histones H3 or H4 [ 38 , 39 , 40 ]. The differences in the enhancement of PARP1 binding to nucleosomes in the presence of different PARPi could be induced by the differences in the network of interactions realized between PARPi and amino acid residues of PARP1 [ 15 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Interactions of PARP1 Inhibitors with PARP1-Nucleosome Complexes

Кошкина

Коровина

Studitsky

et al. 2022

Cells

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Inhibitors (PARPi) of poly(ADP-ribose-)polymerase-1 (PARP1) are used in antitumor therapy; their cytotoxicity correlates with the efficiency of PARP1 trapping in cell chromatin. Previous studies have demonstrated the PARPi-induced trapping of PARP1 on DNA, although details of the mechanism remain controversial. Here, the interactions of PARP1-nucleosome complexes with PARPi, olaparib (Ola), talazoparib (Tala), and veliparib (Veli) were studied. PARPi trap PARP1 on nucleosomes without affecting the structure of PARP1-nucleosome complexes. The efficiency of PARP1 trapping on nucleosomes increases in the order of Tala>Ola>>Veli, recapitulating the relative trapping efficiencies of PARPi in cells, but different from the relative potency of PARPi to inhibit the catalytic activity of PARP1. The efficiency of PARP1 trapping on nucleosomes correlates with the level of inhibition of auto-PARylation, which otherwise promotes the dissociation of PARP1-nucleosome complexes. The trapping efficiencies of Tala and Ola (but not Veli) are additionally modulated by the enhanced PARP1 binding to nucleosomes. The dissociation of PARP1-nucleosome complexes occurs without a loss of histones and leads to the restoration of the intact structure of nucleosomal DNA. The data suggest that the chromatin structure can considerably affect the efficiency of the PARPi action.

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Modeling of the Enzyme—Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1

Cited by 11 publications

References 67 publications

Mechanisms of Nucleosome Reorganization by PARP1

Mechanisms of Nucleosome Reorganization by PARP1

Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di‐Substituted Oxadiazole‐Based Dibenzo‐Azepine‐Dione Derivatives on Poly (ADP‐Ribose) Polymerase‐1

Interactions of PARP1 Inhibitors with PARP1-Nucleosome Complexes

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