scholarly journals G-Quadruplex loops regulate PARP-1 enzymatic activation

2020 ◽  
Author(s):  
Andrea D Edwards ◽  
John C Marecki ◽  
Alicia K Byrd ◽  
Jun Gao ◽  
Kevin D Raney
Keyword(s):  
Dna Repair ◽  
Enzymatic Activity ◽  
Regulation Of Transcription ◽  
Dna Structures ◽  
Repair Enzymes ◽  
G Quadruplex ◽  
Associated Proteins ◽  
Enzymatic Activation ◽  
Forming Characteristics ◽  
Parp 1

Abstract G-Quadruplexes are non-B form DNA structures present at regulatory regions in the genome, such as promoters of proto-oncogenes and telomeres. The prominence in such sites suggests G-quadruplexes serve an important regulatory role in the cell. Indeed, oxidized G-quadruplexes found at regulatory sites are regarded as epigenetic elements and are associated with an interlinking of DNA repair and transcription. PARP-1 binds damaged DNA and non-B form DNA, where it covalently modifies repair enzymes or chromatin-associated proteins respectively with poly(ADP-ribose) (PAR). PAR serves as a signal in regulation of transcription, chromatin remodeling, and DNA repair. PARP-1 is known to bind G-quadruplexes with stimulation of enzymatic activity. We show that PARP-1 binds several G-quadruplex structures with nanomolar affinities, but only a subset promote PARP-1 activity. The G-quadruplex forming sequence found in the proto-oncogene c-KIT promoter stimulates enzymatic activity of PARP-1. The loop-forming characteristics of the c-KIT G-quadruplex sequence regulate PARP-1 catalytic activity, whereas eliminating these loop features reduces PARP-1 activity. Oxidized G-quadruplexes that have been suggested to form unique, looped structures stimulate PARP-1 activity. Our results support a functional interaction between PARP-1 and G-quadruplexes. PARP-1 enzymatic activation by G-quadruplexes is dependent on the loop features and the presence of oxidative damage.

Toxicoproteomic Analysis of Poly(ADP-Ribose)-Associated Proteins Induced by Oxidative Stress in Human Proximal Tubule Cells

2019 ◽  
Vol 171 (1) ◽  
pp. 117-131
Author(s):  
Argel Islas-Robles ◽  
Deepthi Yedlapudi ◽  
Serrine S Lau ◽  
Terrence J Monks
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Proximal Tubule ◽  
Calcium Influx ◽  
Regulation Of Transcription ◽  
Loss Of Function ◽  
Proximal Tubule Cells ◽  
Associated Proteins ◽  
Tubule Cells ◽  
Parp 1

Abstract 2,3,5-Tris-(glutathion-S-yl)hydroquinone (TGHQ) is a nephrotoxic and nephrocarcinogenic metabolite of hydroquinone. TGHQ generates reactive oxygen species (ROS), causing DNA-strand breaks, hyperactivation of PARP-1, increases in intracellular calcium ([Ca2+]i), and cell death. PARP-1 catalyzes the attachment of ADP-ribose polymers (PAR) to target proteins. In human kidney proximal tubule cells, ROS-mediated PARP-1 hyperactivation and elevations in [Ca2+]i are reciprocally coupled. The molecular mechanism of this interaction is unclear. The aim of the present study was to identify ROS-induced PAR-associated proteins to further understand their potential role in cell death. PAR-associated proteins were enriched by immunoprecipitation, identified by LC-MS/MS, and relative abundance was obtained by spectral counting. A total of 356 proteins were PAR-modified following TGHQ treatment. A total of 13 proteins exhibited gene ontology annotations related to calcium. Among these proteins, the general transcription factor II-I (TFII-I) is directly involved in the modulation of [Ca2+]i. TFII-I binding to phospholipase C (PLC) leads to calcium influx via the TRPC3 channel. However, inhibition of TRPC3 or PLC had no effect on TGHQ-mediated cell death, suggesting that their loss of function may be necessary but insufficient to cause cell death. Nevertheless, TGHQ promoted a time-dependent translocation of TFII-I from the nucleus to the cytosol concomitant with a decrease in tyrosine phosphorylation in α/β-TFII-I. Therefore it is likely that ROS have an important impact on the function of TFII-I, such as regulation of transcription, and DNA translesion synthesis. Our data also shed light on PAR-mediated signaling during oxidative stress, and contributes to the development of strategies to prevent PAR-dependent cell death.

scholarly journals Identification of Novel Interaction Partners of Ets-1: Focus on DNA Repair

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 206
Author(s):  
Guillaume Brysbaert ◽  
Jérôme de Ruyck ◽  
Marc Aumercier ◽  
Marc F. Lensink
Keyword(s):  
Dna Repair ◽  
Interaction Model ◽  
Protein Docking ◽  
Dna Repair Enzymes ◽  
Dna Repair Mechanisms ◽  
Repair Enzymes ◽  
Repair Mechanisms ◽  
Important Regulator ◽  
Dependent Protein ◽  
Parp 1

The transcription factor Ets-1 (ETS proto-oncogene 1) shows low expression levels except in specific biological processes like haematopoiesis or angiogenesis. Elevated levels of expression are observed in tumor progression, resulting in Ets-1 being named an oncoprotein. It has recently been shown that Ets-1 interacts with two DNA repair enzymes, PARP-1 (poly(ADP-ribose) polymerase 1) and DNA-PK (DNA-dependent protein kinase), through two different domains and that these interactions play a role in cancer. Considering that Ets-1 can bind to distinctly different domains of two DNA repair enzymes, we hypothesized that the interaction can be transposed onto homologs of the respective domains. We have searched for sequence and structure homologs of the interacting ETS(Ets-1), BRCT(PARP-1) and SAP(DNA-PK) domains, and have identified several candidate binding pairs that are currently not annotated as such. Many of the Ets-1 partners are associated to DNA repair mechanisms. We have applied protein-protein docking to establish putative interaction poses and investigated these using centrality analyses at the protein residue level. Most of the identified poses are virtually similar to our recently established interaction model for Ets-1/PARP-1 and Ets-1/DNA-PK. Our work illustrates the potentially high number of interactors of Ets-1, in particular involved in DNA repair mechanisms, which shows the oncoprotein as a potential important regulator of the mechanism.

scholarly journals The Relevance of G-Quadruplexes for DNA Repair

2021 ◽  
Vol 22 (22) ◽  
pp. 12599
Author(s):  
Rebecca Linke ◽  
Michaela Limmer ◽  
Stefan Juranek ◽  
Annkristin Heine ◽  
Katrin Paeschke
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genome Instability ◽  
Genetic Disorders ◽  
Telomere Maintenance ◽  
Dna Structures ◽  
G4 Dna ◽  
G Quadruplex ◽  
Repair Pathways

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

PARPi in PCa results in decreased availability of DNA repair factors.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 301-301
Author(s):  
Matthew Joseph Schiewer ◽  
Karen E. Knudsen
Keyword(s):  
Dna Repair ◽  
Enzymatic Activity ◽  
Disease Progression ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Clinical Trial Data ◽  
Parp Inhibition ◽  
Transcriptional Regulatory ◽  
Parp 1

301 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).

scholarly journals Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function

2019 ◽  
Vol 26 (12) ◽  
pp. 2667-2681 ◽  
Author(s):  
Miguel A. Galindo-Campos ◽  
Marie Bedora-Faure ◽  
Jordi Farrés ◽  
Chloé Lescale ◽  
Lucia Moreno-Lama ◽  
...  
Keyword(s):  
Dna Repair ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Dna Repair Enzymes ◽  
Repair Enzymes ◽  
And Function ◽  
Parp 1

scholarly journals Sensitizing Ewing sarcoma to chemo- and radiotherapy by inhibition of the DNA-repair enzymes DNA protein kinase (DNA-PK) and poly-ADP-ribose polymerase (PARP) 1/2

Oncotarget ◽  
2017 ◽  
Vol 8 (69) ◽  
pp. 113418-113430 ◽  
Author(s):  
Britta Vormoor ◽  
Yvonne T. Schlosser ◽  
Helen Blair ◽  
Abhishek Sharma ◽  
Sarah Wilkinson ◽  
...  
Keyword(s):  
Dna Repair ◽  
Protein Kinase ◽  
Ewing Sarcoma ◽  
Dna Repair Enzymes ◽  
Repair Enzymes ◽  
Parp 1

scholarly journals G‐Quadruplex Loop Length Regulates PARP‐1 Enzymatic Activation

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Andrea Edwards ◽  
John Marecki ◽  
Alicia Byrd ◽  
Kevin Raney
Keyword(s):  
Loop Length ◽  
G Quadruplex ◽  
Enzymatic Activation ◽  
Parp 1

EFFECT OF MMSC AND HSC ON REPARATIVE REGENERATION OF THE LIVER UNDER CONDITIONS OF ITS TOXIC DAMAGE

2020 ◽  
Vol 17 (3) ◽  
pp. 243-248
Author(s):  
I.Yu. Maklakova ◽  
◽  
V.V. Bazarniy ◽  
D.Yu. Grebnev ◽  
◽  
...  
Keyword(s):  
Dna Repair ◽  
Carbon Tetrachloride ◽  
Mitotic Activity ◽  
Liver Damage ◽  
Inflammatory Activity ◽  
Control Group ◽  
Nacl Solution ◽  
Repair Enzymes ◽  
Toxic Liver Damage ◽  
Hsc Transplantation

The aim of this study was to study the effect of combined MMSC and HSC transplantation on liver regeneration under conditions of toxic carbon tetrachloride damage. Materials and methods. The study was performed on white male mice with toxic liver damage by intraperitoneal administration of carbon tetrachloride at a dose of 50 µl per mouse once. An hour after modeling liver damage, placental MMSCs and HSCs were administered intravenously at a dose of 4 million cells/kg and 330 thousand cells/kg, respectively, suspended in 0.2 ml of 0.9% NaCl solution. Control group animals were given 0.9% NaCl solution-0.2 ml intravenously. On days 1, 3, and 7 after cell transplantation, changes in inflammatory activity in the liver were evaluated, and mitotic and apoptotic indices were determined. On the 7th day after the introduction of cells, the activity of DNA repair enzymes of the PARP family was analyzed. Results. Combined MMSC and HSC transplantation leads to a decrease in the index of inflammatory activity in the liver due to a decrease in necrosis, hepatocyte dystrophy, and a decrease in infiltration. As a result of the study, an increase in the activity of PARP repair enzymes was found, which led to a decrease in programmed cell death. Also, cotransplantation of MMSCs and HSCs was accompanied by increased mitotic activity of hepatocytes. Conclusion. Cotransplantation of MMSCs and HSCs under conditions of toxic liver damage reduces the inflammatory response, stimulates the mitotic activity of hepatocytes, and increases the activity of enzymes of the DNA repair system. Activation of the liver's reparative system, in turn, reduces the programmed death of hepatocytes.

scholarly journals Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design, synthesis and antitumor activity

RSC Advances ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 4454-4464
Author(s):  
Nour E. A. Abd El-sattar ◽  
Eman H. K. Badawy ◽  
Eman Z. Elrazaz ◽  
Nasser S. M. Ismail
Keyword(s):  
Cell Death ◽  
Dna Repair ◽  
Antitumor Activity ◽  
Cancer Cell ◽  
Cytotoxic Agents ◽  
Repair Mechanism ◽  
Design Synthesis ◽  
Parp 1

PARP-1 are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death.

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