Dynamics of endogenous PARP1 and PARP2 during DNA damage revealed by live-cell single-molecule imaging

Mahadevan, Jyothi; Jha, Asmita; Rudolph, Johannes; Bowerman, Samuel; Narducci, Domenic; Hansen, Anders S.; Luger, Karolin

doi:10.1016/j.isci.2022.105779

Cited by 12 publications

(2 citation statements)

References 89 publications

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“…84 Moreover, some PARP inhibitors have demonstrated the ability to trap PARP1 and PARP2 on chromosomal DNA-damaging sites, resulting in the formation of PARP-DNA complexes. 85 This phenomenon, known as "PARP trapping", interferes with the recruitment of DNA repair enzymes, 86 leading to mitotic catastrophe and subsequent cell death by aberrant DNA replication in the absence of proper DNA repair. 87 This synergistic effect is observed not only with PARP inhibitors but also with alkylating agents and platinum-based agents.…”

Section: Discussionmentioning

confidence: 99%

Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway

Bae,

Kim

et al. 2024

CMAR

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Background: Ovarian cancer is one of women's malignancies with the highest mortality among gynecological cancers. Paclitaxel is used in first-line ovarian cancer chemotherapy. Research on paclitaxel-resistant ovarian cancer holds significant clinical importance. Methods: Cell viability and flow cytometric assays were conducted at different time and concentration points of deguelin and paclitaxel treatment. Immunoblotting was performed to assess the activation status of key signaling molecules important for cell survival and proliferation following treatment with deguelin and paclitaxel. The fluo-3 acetoxymethyl assay for P-glycoprotein transport activity assay and cell viability assay in the presence of N-acetyl-L-cysteine were also conducted. Results: Cell viability and flow cytometric assays demonstrated that deguelin resensitized paclitaxel in a dose-and time-dependent manner. Cotreatment with deguelin and paclitaxel inhibited EGFR and its downstream signaling molecules, including AKT, ERK, STAT3, and p38 MAPK, in SKOV3-TR cells. Interestingly, cotreatment with deguelin and paclitaxel suppressed the expression level of EGFR via the lysosomal degradation pathway. Cotreatment did not affect the expression and function of P-glycoprotein. N-acetyl-L-cysteine failed to restore cell cytotoxicity when used in combination with deguelin and paclitaxel in SKOV3-TR cells. The expression of BCL-2, MCL-1, and the phosphorylation of the S155 residue of BAD were downregulated. Moreover, inhibition of paclitaxel resistance by deguelin was also observed in HeyA8-MDR cells. Conclusion: Our research showed that deguelin effectively suppresses paclitaxel resistance in SKOV3-TR ovarian cancer cells by downregulating the EGFR and its downstream signaling pathway and modulating the BCL-2 family proteins. Furthermore, deguelin exhibits inhibitory effects on paclitaxel resistance in HeyA8-MDR ovarian cancer cells, suggesting a potential mechanism for paclitaxel resensitization that may not be cell-specific. These findings suggest that deguelin holds promise as an anticancer therapeutic agent for overcoming chemoresistance in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway

Bae,

Kim

et al. 2024

CMAR

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“…This phenomenon is well understood in the context of DNA damage and repair, where PARP1 acts as a guardian or surveyor of the genome [ 1 ]. PARP1 is dynamically distributed on chromatin where it constantly scans the DNA [ 2 ]. The recognition of DNA damage by PARP1, for which it has high affinity, results in acute PARylation [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

PARP1 Regulates Circular RNA Biogenesis though Control of Transcriptional Dynamics

Eleazer

Silva

Andreeva

et al. 2023

Cells

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Circular RNAs (circRNAs) are a recently discovered class of RNAs derived from protein-coding genes that have important biological and pathological roles. They are formed through backsplicing during co-transcriptional alternative splicing; however, the unified mechanism that accounts for backsplicing decisions remains unclear. Factors that regulate the transcriptional timing and spatial organization of pre-mRNA, including RNAPII kinetics, the availability of splicing factors, and features of gene architecture, have been shown to influence backsplicing decisions. Poly (ADP-ribose) polymerase I (PARP1) regulates alternative splicing through both its presence on chromatin as well as its PARylation activity. However, no studies have investigated PARP1’s possible role in regulating circRNA biogenesis. Here, we hypothesized that PARP1’s role in splicing extends to circRNA biogenesis. Our results identify many unique circRNAs in PARP1 depletion and PARylation-inhibited conditions compared to the wild type. We found that while all genes producing circRNAs share gene architecture features common to circRNA host genes, genes producing circRNAs in PARP1 knockdown conditions had longer upstream introns than downstream introns, whereas flanking introns in wild type host genes were symmetrical. Interestingly, we found that the behavior of PARP1 in regulating RNAPII pausing is distinct between these two classes of host genes. We conclude that the PARP1 pausing of RNAPII works within the context of gene architecture to regulate transcriptional kinetics, and therefore circRNA biogenesis. Furthermore, this regulation of PARP1 within host genes acts to fine tune their transcriptional output with implications in gene function.

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Live cell single-molecule imaging to study DNA repair in human cells

2023

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Dynamics of endogenous PARP1 and PARP2 during DNA damage revealed by live-cell single-molecule imaging

Cited by 12 publications

References 89 publications

Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway

Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway

PARP1 Regulates Circular RNA Biogenesis though Control of Transcriptional Dynamics

Live cell single-molecule imaging to study DNA repair in human cells

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