Suppressing the NHEJ pathway by DNA-PKcs inhibitor NU7026 prevents degradation of HBV cccDNA cleaved by CRISPR/Cas9

Kostyushev, Dmitry; Kostyusheva, Anastasiya; Brezgin, Sergey; Zarifyan, Dmitry; Utkina, Anastasiya; Goptar, Irina A.; Chulanov, Vladimir

doi:10.1038/s41598-019-38526-6

Cited by 42 publications

(34 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional experiments are needed to rule out whether cellular effects such as cell division, migration, or differentiation are affected in long term tissue renewal. The homeostatic effects of PARylation may be overshadowed by the dominant suppression of alternative enjoining through the core DNA repair signaling pathways (i.e., nonhomologous end joining and homologous recombination) [55][56][57]. Nonetheless, the finding that Smed-PARP-3 is a regulator of regeneration is consistent with our previous work, where we found its expression sharply activated within the first three hours post-injury [20] and recent findings by the Aboobaker group [22].…”

Section: Discussionsupporting

confidence: 91%

Poly(ADP-Ribose) Polymerase-3 Regulates Regeneration in Planarians

Barghouth

Karabinis

Venegas

et al. 2020

IJMS

View full text Add to dashboard Cite

Protein ADP-ribosylation is a reversible post-translational modification (PTM) process that plays fundamental roles in cell signaling. The covalent attachment of ADP ribose polymers is executed by PAR polymerases (PARP) and it is essential for chromatin organization, DNA repair, cell cycle, transcription, and replication, among other critical cellular events. The process of PARylation or polyADP-ribosylation is dynamic and takes place across many tissues undergoing renewal and repair, but the molecular mechanisms regulating this PTM remain mostly unknown. Here, we introduce the use of the planarian Schmidtea mediterranea as a tractable model to study PARylation in the complexity of the adult body that is under constant renewal and is capable of regenerating damaged tissues. We identified the evolutionary conservation of PARP signaling that is expressed in planarian stem cells and differentiated tissues. We also demonstrate that Smed-PARP-3 homolog is required for proper regeneration of tissues in the anterior region of the animal. Furthermore, our results demonstrate, Smed-PARP-3(RNAi) disrupts the timely location of injury-induced cell death near the anterior facing wounds and also affects the regeneration of the central nervous system. Our work reveals novel roles for PARylation in large-scale regeneration and provides a simplified platform to investigate PARP signaling in the complexity of the adult body.

show abstract

Section: Discussionsupporting

confidence: 91%

Poly(ADP-Ribose) Polymerase-3 Regulates Regeneration in Planarians

Barghouth

Karabinis

Venegas

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…HBV-DNA can be integrated into host genomic DNA and cause insertion mutations or other genomic instabilities [38,39]. Studies have shown that DNA double strand breaks (DSBs) induced by DNA damage are potential targets for HBV-DNA integration [40][41][42]. The body repairs DSBs through two major repair pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ) [43].…”

Section: Discussionmentioning

confidence: 99%

EXO1 Plays a Carcinogenic Role in Hepatocellular Carcinoma and is related to the regulation of FOXP3

Yang¹,

Dong²,

Zhang³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Exonuclease 1 (EXO1), a member of the RAD2 nuclease family, was first described as possessing 5' to 3' nuclease activity and 5' structure-specific endonuclease activity. Here, we show that EXO1 is significantly upregulated in HCC tumor tissues and that high EXO1 expression is significantly correlated with liver cirrhosis. We further demonstrate that EXO1 knockdown decreases proliferation and colony forming abilities of HCC cells in vitro and tumorigenicity in vivo, as well as decreases migration and invasive capabilities of HCC cells. Alternatively, EXO1 overexpression significantly increases the proliferation, colony forming ability, and migration and invasive capabilities of HCC cells in vitro. Additionally, we truncated a region upstream of the transcription start site (TSS) of EXO1 and used the region with the strongest transcriptional activity to predict that the transcription factor FOXP3 can bind to the EXO1 promoter. Bioinformatics analysis found that FOXP3 was positively correlated with EXO1 and luciferase reporter assays and RT-PCR confirmed that FOXP3 could enhance the transcriptional activity of EXO1. CCK-8 assays showed that depletion of FOXP3 further reduces cell proliferation ability after knocking down of EXO1 in vitro. Taken together, our findings indicate that EXO1 acts as an oncogene in HCC and its expression level is related to FOXP3 activity.

show abstract

“…Hence, HBV cccDNA is an optimal target for nuclease gene editing, due to its episomal minichromosome configuration and sequence stability. More specifically, the efficacy of CRISPR/Cas9 for cleavage and inactivation of the cccDNA, as well as inhibition of hepatocarcinogenesis, has been reported [ 34 , 35 ].…”

Section: Direct Acting Antiviralsmentioning

confidence: 99%

New Approaches to the Treatment of Chronic Hepatitis B

Alexopoulou

Vasilieva

Karayiannis

2020

JCM

View full text Add to dashboard Cite

The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

show abstract

Suppressing the NHEJ pathway by DNA-PKcs inhibitor NU7026 prevents degradation of HBV cccDNA cleaved by CRISPR/Cas9

Cited by 42 publications

References 68 publications

Poly(ADP-Ribose) Polymerase-3 Regulates Regeneration in Planarians

Poly(ADP-Ribose) Polymerase-3 Regulates Regeneration in Planarians

EXO1 Plays a Carcinogenic Role in Hepatocellular Carcinoma and is related to the regulation of FOXP3

New Approaches to the Treatment of Chronic Hepatitis B

Contact Info

Product

Resources

About