Functional Aspects of PARP1 in DNA Repair and Transcription

Ko, Hui Ling; Ren, Ee Chee

doi:10.3390/biom2040524

Cited by 161 publications

(137 citation statements)

References 158 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…PARP-1 has diverse functions, including DNA repair, cell cycle control, apoptosis, and gene expression (5)(6)(7)32). In addition, PARP-1 has been shown to inhibit the lytic replication of KSHV and MHV-68 (8-10, 12, 33).…”

Section: Discussionmentioning

confidence: 99%

“…Several cellular factors are known to regulate the lytic replication of gammaherpesvirus, ultimately contributing to viral pathogenesis (3,4). Poly(ADP-ribose) polymerase 1 (PARP-1) is an abundant nuclear protein that catalyzes the poly(ADP-ribosyl)ation of target proteins acting in DNA repair, cell cycle control, apoptosis, and gene expression (5)(6)(7). In KSHV and MHV-68 infections, PARP-1 interacts with the poly(ADP-ribosyl)ate replication and transcription activator (RTA), the molecular switch of lytic replication, thereby repressing lytic viral replication (8)(9)(10)(11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus

Cheong

Park

Kang

et al. 2015

J Virol

View full text Add to dashboard Cite

In Kaposi's sarcoma-associated herpesvirus (KSHV), poly(ADP-ribose) polymerase 1 (PARP-1) acts as an inhibitor of lytic replication. Here, we demonstrate that KSHV downregulated PARP-1 upon reactivation. The viral processivity factor of KSHV (PF-8) interacted with PARP-1 and was sufficient to degrade PARP-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. PF-8 knockdown in KSHV-infected cells resulted in reduced lytic replication upon reactivation with increased levels of PARP-1, compared to those in control cells. PF-8 overexpression reduced the levels of the poly(ADPribosyl)ated (PARylated) replication and transcription activator (RTA) and further enhanced RTA-mediated transactivation. These results suggest a novel viral mechanism for overcoming the inhibitory effect of a host factor, PARP-1, thereby promoting the lytic replication of gammaherpesvirus. IMPORTANCEGammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors and establish latency mainly in host B lymphocytes. Replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is a central molecular switch for lytic replication, and its expression is tightly regulated by many host and viral factors. In this study, we investigated a viral strategy to overcome the inhibitory effect of poly(ADP-ribose) polymerase 1 (PARP-1) on RTA's activity. PARP-1, an abundant multifunctional nuclear protein, was downregulated during KSHV reactivation. The viral processivity factor of KSHV (PF-8) directly interacted with PARP-1 and was sufficient and necessary to degrade PARP-1 protein in a proteasome-dependent manner. PF-8 reduced the levels of PARylated RTA and further promoted RTA-mediated transactivation. As this was also conserved in another gammaherpesvirus, murine gammaherpesvirus 68, our results suggest a conserved viral modulation of a host inhibitory factor to facilitate its lytic replication. Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and murine gammaherpesvirus 68 (MHV-68), are associated with various malignancies and lymphoproliferative disorders (1, 2). Several cellular factors are known to regulate the lytic replication of gammaherpesvirus, ultimately contributing to viral pathogenesis (3, 4). Poly(ADP-ribose) polymerase 1 (PARP-1) is an abundant nuclear protein that catalyzes the poly(ADP-ribosyl)ation of target proteins acting in DNA repair, cell cycle control, apoptosis, and gene expression (5-7). In KSHV and MHV-68 infections, PARP-1 interacts with the poly(ADP-ribosyl)ate replication and transcription activator (RTA), the molecular switch of lytic replication, thereby repressing lytic viral replication (8-11). PARP-1 is also known to be a component of the viral replication complex, increasing viral genome replication (9, 12). Previously, we showed that open reading frame 49 (ORF49) of MHV-68 interacts with PARP-1, disrupting interactions between RTA and PARP-1 and furthe...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus

Cheong

Park

Kang

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…PARP repairs DNA strand breaks, and caspase-3 cleavage of PARP into 85-and 25-kDa fragments prevents its DNA repair function during apoptosis (66). The 85-kDa fragment also has been reported to modulate pro-apoptotic molecules such as p53 (67).…”

Section: Cell Growth Inhibition and Apoptosis Inductionmentioning

confidence: 99%

Temporal Effects of Combined Birinapant and Paclitaxel on Pancreatic Cancer Cells Investigated via Large-Scale, Ion-Current-Based Quantitative Proteomics (IonStar)

Wang

Niu

Li³

et al. 2018

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

SummaryDespite decades of effort, pancreatic adenocarcinoma (PDAC) remains an intractable clinical challenge.An insufficient understanding of mechanisms underlying tumor cell responses to chemotherapy contributes significantly to the lack of effective treatment regimens. Here, paclitaxel, a first-line chemotherapeutic agent, was observed to interact synergistically with birinapant, a Second Mitochondrial-derived Activator of Caspases mimetic. Therefore, we investigated molecular-level drug interaction mechanisms using comprehensive, reproducible, and well-controlled ion-current-based MS1 quantification (IonStar). By analyzing 40 biological samples in a single batch, we compared temporal proteomic responses of PDAC cells treated with birinapant and paclitaxel, alone and combined. Using stringent criteria (e.g. strict false-discovery-rate FDR control, 2 peptides/protein), we quantified 4069 unique proteins confidently (99.8% without any missing data), and 541 proteins were significantly altered in the three treatment groups, with a FDR of <1%. Interestingly, most of these proteins were altered only by combined birinapant/paclitaxel, and these predominantly represented three biological processes: mitochondrial function, cell growth and apoptosis, and cell cycle arrest. Proteins responsible for activation of oxidative phosphorylation, fatty acid β-oxidation, and inactivation of aerobic glycolysis were altered largely by combined birinapant/paclitaxel compared to single drugs, suggesting the Warburg effect, which is critical for survival and proliferation of cancer cells, was alleviated by the combination treatment. Metabolic profiling was performed to confirm substantially greater suppression of the Warburg effect by the combined agents compared to either drug alone. Immunoassays confirmed proteomic data revealing changes in apoptosis/survival signaling pathways, such as inhibition of PI3K/AKT, JAK/STAT, and MAPK/ERK signal transduction, as well as induction of G2/M arrest, and showed the drug combination induced much more apoptosis than did single agents. Overall, this in-depth, large-scale proteomics study provided novel insights into molecular mechanisms underlying synergy of combined birinapant/paclitaxel, and describes a proteomics/informatics pipeline that can be applied broadly to the development of cancer drug combination regimens.4

show abstract

“…Inhibition of Parp-1 results in an increase in single strand breaks (SSBs) that then collapse replication forks into toxic one-ended DSBs [1,2], which are substrates for HR [3,4]. In addition, through enzymedependent chromatin remodeling and enzyme-independent motif recognition, Parp-1 also plays important roles in regulating gene expression [5]. Furthermore, Parp-1 binding motifs may be readily found in promoter elements of DNA repair genes, linking DNA repair and transcription functions of Parp-1 [5].…”

Section: Research Papermentioning

confidence: 99%

Untitled

2017

Oncotarget

View full text Add to dashboard Cite

Mutations in DNA repair pathways are frequent in human cancers. Hence, gaining insights into the interaction of DNA repair genes is key to development of novel tumor-specific treatment strategies. In this study, we tested the functional relationship in development and oncogenesis between the homologous recombination (HR) factor Rad54 and Parp-1, a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. We introduced single or combined Rad54

show abstract

Functional Aspects of PARP1 in DNA Repair and Transcription

Cited by 161 publications

References 158 publications

Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus

Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus

Temporal Effects of Combined Birinapant and Paclitaxel on Pancreatic Cancer Cells Investigated via Large-Scale, Ion-Current-Based Quantitative Proteomics (IonStar)

Untitled

Contact Info

Product

Resources

About