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effect of UCN-01 on the cell cycle distribution and cell death in cells treated with veliparib plus topotecan. after 24 h exposure to veliparib plus topotecan, the cultures were washed, and UCN-01 (100 nM) or vehicle was added for an additional 18 h. (a) Cell cycle effects of veliparib in combination with topotecan in the presence and absence of UCN-01. The numbers above G 1 and G 2 peaks indicate the percentage of cells in each phase of the cell cycle. (B) percent change, relative to vehicle treatment without UCN-01, of cell death by veliparib plus topotecan without UCN-01 (gray bar), and with UCN-01(black bar) assessed by clonogenic assays. shown are the representative data of two independent experiments. aBT, aBT-888; TpT, topotecan.
Source publication
Targeting DNA repair with poly(ADP-ribose) polymerase (PARP) inhibitors has shown a broad range of anti-tumor activity in patients with advanced malignancies with and without BRCA deficiency. It remains unclear what role p53 plays in response to PARP inhibition in BRCA-proficient cancer cells treated with DNA damaging agents. Using gene expression...
Contexts in source publication
Context 1
... inhibition augments cancer cell apoptosis and death induced by topotecan in p53-wild-type and p53-mutant or -null cells. We also sought to examine whether this combina- tion approach leads to the enhancement of subsequent cancer cell death and apoptosis. PARP cleavage, which is indicative of cells undergoing apoptosis, was detectable 96 h after exposure to topotecan alone and to the two drug combination (Fig. 2A). PARP inhibition markedly enhanced topotecan-induced cancer cell death (measured as the reduced clonogenic cell survival) in p53-wild-type, as well as p53-null or -mutant cancer cells (all p ≤ 0.05, unpaired two-sided t-test; Fig. 2B). Noticeably, there were comparable enhancement of cell death by veliparib in HCT116 p53 +/+ and p53 -/-cells (45.8% vs. 43.0%; Fig. 2B). In addition, varying levels of enhancement of cell death were observed in p53-mutant MDA-231 and HT-29 cells. In all cases, G 2 arrest by veliparib, topotecan and veliparib plus topotecan was associated with the death of cancer cells (Spearman's correlation coefficient = 0.70, p = 0.004; Fig. 2C). These data indicate that veliparib augments the death of cancer cells induced by topote- can. G 2 arrest, despite not being causal for the cell death, reflects the collective DNA damage effects induced by the drug treat- ments. p53 deficiency alone does not appear to specifically confer more sensitivity or resistance to treatment with a PARP inhibitor plus topotecan or with topotecan alone (Fig. 2B). UCN-01 abrogates G 2 arrest induced by veliparib plus topo- tecan in p53-wild-type and p53-mutant cells. UCN-01, a cell cycle checkpoint kinase inhibitor, has been shown to abrogate the cell cycle checkpoints induced by DNA damaging drugs. 28,29 To study whether UCN-01 abolishes the cell cycle G 2 arrest induced by drug treatments and further enhances cell death, we performed cell cycle analysis in cells treated with veliparib plus topotecan in the presence and absence of UCN-01. UCN-01 at low dose (100 nM) nearly abrogated G 2 arrest induced by veliparib plus topotecan in p53-wild-type HCT-116 and p53-mutant HT-29 cells relative to the cells treated without UCN-01 ( Fig. 3A). Importantly, UCN-01 further increased cell death (Fig. 3B). p53 status. We find that PARP inhibition markedly enhances the cellular DNA damage responses by alteration of multiple DNA damage response pathways and the death of cancer cells in a p53-dependent and -independent manner. The alteration and activation of crucial cell cycle-related genes across the identified pathways in association with DNA damage responses have been validated and are discussed. (Table S1A). More tran- scripts, in contrast, were significantly upregulated by the combi- nation treatment. Those included PA26, DDB2, Bax, FasR and MDM2 in addition to p21 CDKN1A and BTG2 (Table S1B). In p53 -/- cells, no changes were detected in the context of DNA damage response by topotecan alone (Table S1C), whereas veliparib plus topotecan treatment induced RAD51, a critical DSB repair gene, and CDC2 as well as CDC6 (Table S1D). 27 Therefore, the veli- parib and topotecan combination induces more significant gene expression alterations relevant to DNA damage response than topotecan alone, and those alterations are both dependent and independent of ...
Context 2
... inhibition augments cancer cell apoptosis and death induced by topotecan in p53-wild-type and p53-mutant or -null cells. We also sought to examine whether this combina- tion approach leads to the enhancement of subsequent cancer cell death and apoptosis. PARP cleavage, which is indicative of cells undergoing apoptosis, was detectable 96 h after exposure to topotecan alone and to the two drug combination (Fig. 2A). PARP inhibition markedly enhanced topotecan-induced cancer cell death (measured as the reduced clonogenic cell survival) in p53-wild-type, as well as p53-null or -mutant cancer cells (all p ≤ 0.05, unpaired two-sided t-test; Fig. 2B). Noticeably, there were comparable enhancement of cell death by veliparib in HCT116 p53 +/+ and p53 -/-cells (45.8% vs. 43.0%; Fig. 2B). In addition, varying levels of enhancement of cell death were observed in p53-mutant MDA-231 and HT-29 cells. In all cases, G 2 arrest by veliparib, topotecan and veliparib plus topotecan was associated with the death of cancer cells (Spearman's correlation coefficient = 0.70, p = 0.004; Fig. 2C). These data indicate that veliparib augments the death of cancer cells induced by topote- can. G 2 arrest, despite not being causal for the cell death, reflects the collective DNA damage effects induced by the drug treat- ments. p53 deficiency alone does not appear to specifically confer more sensitivity or resistance to treatment with a PARP inhibitor plus topotecan or with topotecan alone (Fig. 2B). UCN-01 abrogates G 2 arrest induced by veliparib plus topo- tecan in p53-wild-type and p53-mutant cells. UCN-01, a cell cycle checkpoint kinase inhibitor, has been shown to abrogate the cell cycle checkpoints induced by DNA damaging drugs. 28,29 To study whether UCN-01 abolishes the cell cycle G 2 arrest induced by drug treatments and further enhances cell death, we performed cell cycle analysis in cells treated with veliparib plus topotecan in the presence and absence of UCN-01. UCN-01 at low dose (100 nM) nearly abrogated G 2 arrest induced by veliparib plus topotecan in p53-wild-type HCT-116 and p53-mutant HT-29 cells relative to the cells treated without UCN-01 ( Fig. 3A). Importantly, UCN-01 further increased cell death (Fig. 3B). p53 status. We find that PARP inhibition markedly enhances the cellular DNA damage responses by alteration of multiple DNA damage response pathways and the death of cancer cells in a p53-dependent and -independent manner. The alteration and activation of crucial cell cycle-related genes across the identified pathways in association with DNA damage responses have been validated and are discussed. (Table S1A). More tran- scripts, in contrast, were significantly upregulated by the combi- nation treatment. Those included PA26, DDB2, Bax, FasR and MDM2 in addition to p21 CDKN1A and BTG2 (Table S1B). In p53 -/- cells, no changes were detected in the context of DNA damage response by topotecan alone (Table S1C), whereas veliparib plus topotecan treatment induced RAD51, a critical DSB repair gene, and CDC2 as well as CDC6 (Table S1D). 27 Therefore, the veli- parib and topotecan combination induces more significant gene expression alterations relevant to DNA damage response than topotecan alone, and those alterations are both dependent and independent of ...
Context 3
... combination treatment also widens the cellular DNA damage responses in cancer cells with endogenous wild-type as well as mutant p53 gene. Veliparib plus topotecan elicits p53, ATM signaling and G 1 /S checkpoint pathways relative to the latter pathway by topotecan alone (Table S2A and S2B). The three pathways comprise an array of highly coordinated genes with interrelated functions on the cell cycle checkpoints, DNA damage response signaling, DNA repair and apoptosis. The differentially expressed genes in role of BRCa1, BRCa2 and aTR in cancer susceptibility pathway* by veliparib plus topotecan in p53-mutant lines In summary, our findings using a gene expression profiling approach delineate the cellular responses to the combination of a PARP inhibitor and a DNA damaging agent in p53-proficient and -deficient, and BRCA-proficient cancer cells. The results increase our understanding of how PARP inhibition augments p53-mutant HT-29 cells, which led to a further increase in cell death (Fig. 3B). Thus, abrogation of the cell cycle arrest, which is a conserved protective means of cells, further sensitizes the cancer cells to the veliparib and topotecan combination treatment. To identify significantly changed transcripts in the pair of HCT-116 p53 +/+ and p53 -/-, each probe set on the drug-treated array (11 probes per probe-set) was compared with the corre- sponding vehicle-treated one using Wilcoxon's signed rank test. It was defined as statistically significant if p < 0.003 for increase and p > 0.997 for decrease in expression by Affymetrix MAS 5.0 Statistical Comparison Analysis in GCOS. 40 Protein gel blots. Equal numbers of cells were lysed in Laemmli sample buffer and subjected to electrophoresis. 44 Nitrocellulose filters were probed with antibodies to p21 in 1:200 dilution (clone DO7, Santa Cruz Inc.), to phospho- Chk1 (Ser345), phospho-Chk2 (Thr68), phosphorylated his- tone H3 and cleaved PARP in 1:1,000 dilutions (Cell Signaling Technology), respectively. β-actin was probed as the protein loading control (antibody dilution 1:5,000; Sigma). Reactive the efficacy of DNA damaging agents. They may have implica- tions for the design of treatment strategies by pharmacological PARP inhibition using small molecule PARP inhibitors in com- bination with additional agents that specifically target the key members of cell cycle checkpoints in the treatment of BRCA- proficient ...
Citations
... Cell cycle analysis has been described previously 31 . In brief, cells were treated with DNMTi. ...
Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene deletion/disruption (DNMT1−/−) on anticancer activity of a class of DNMTi in vitro, in vivo and in human cancers. The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4′-thio-2′-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. The drugs induced DNA damage that concurred with DNMT1 inhibition, subsequent G2/M cell-cycle arrest and apoptosis, and upregulated p21 in DNMT1+/+ versus DNMT1−/− status, with aza-T-dCyd the most potent. Tumor growth and DNMT1 were significantly inhibited, and p21 was upmodulated in mice bearing HCT116 DNMT1+/+ xenograft and bladder PDX tumors. DNMT1 gene deletion occurred in ~ 9% human colon cancers and other cancer types at varying degrees. Decitabine and azacitidine demethylated CDKN2A/CDKN2B genes in DNMT1+/+ and DNMT1−/− conditions and increased histone-H3 acetylation with re-expression of p16INK4A/p15INK4B in DNMT1−/− state. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment.
... Activation of p53 could also contributes to SNAI2 induction 14 . PARP inhibitors have been reported to induce and potentiate p53 activation 43,44 . To test the potential involvement of p53, we efficiently knocked down p53 by siRNA and observed that Talazoparib-induced SNAI2 induction was not attenuated (Fig. S5e,f), thus we could exclude the possibility that SNAI2 induction was due to p53 activation. ...
The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.
... However, in some cases, the presence of mutp53 may turn out to be an Achilles's heel, as, for example, the R273H p53 mutation has been reported to render breast cancer cells more susceptible to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors [3]. However, regarding this topic, there are contradictory studies, including our own performed on colon cancer, which suggests that mutp53 could counteract the cytotoxicity of PARP inhibitors rather than increase it [4] or not influence the PARP inhibitor treatment at all [5]. It seems that, depending on the specific cellular contexts, mutp53 may differently influence the response of cancer cells to PARP inhibitor treatment. ...
HDAC inhibitors (HDACi) represent promising anti-cancer treatments, as the acetylation of histone and non-histone proteins is often dysregulated in cancer and contributes to cancer onset and progression. HDACi have been also reported to increase the cytotoxicity of DNA-damaging agents, such as radiation or cisplatin. In this study, we found that TSA and, even more effectively, VPA synergized with AZD2461, PARP1, 2 and 3 inhibitor (PARPi) to induce DNA damage and reduce pancreatic cancer cell survival. At a molecular level, VPA and TSA down-regulated CHK1 and RAD51, which is correlated with the interruption of the cross-talk between mutp53 and HSP70. Moreover, VPA and to a lesser extent TSA reactivated wtp53 in these cells, which contributed to CHK1 and RAD51 reduction. These findings suggest that the combination of HDACi and PARPi might improve the treatment of pancreatic cancer, which remains one of the most aggressive and therapy-resistant cancers.
... After 48 h of drug treatment, 2000 cells were washed and plated into 6-well plates with each condition in triplicate as described previously [24]. After 10-14 days, colonies were fixed in 10% methanol 10% acetic acid glacial solution and, following wash, stained with 0.1% crystal violet in plates. ...
Background
Challenges remain on the selection of patients who potentially respond to a class of drugs that target epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models.
Methods
Seventeen cancer cell lines and multiple xenograft models bearing representative human solid tumors were subjected to 4′-thio-2′-deoxycytidine (T-dCyd) or control treatment. Gene mutations in cell lines were examined by whole exome and/or Sanger sequencing. Specific gene expression was measured in cells and xenograft tumor samples by Western blotting and immunohistochemistry. TET2/DNMT3A mutation status in 47,571 human tumor samples was analyzed at cBioPortal for Cancer Genomics.
Results
Cell survival was significantly inhibited by T-dCyd in breast BT549, lung NCI-H23, melanoma SKMEL5 and renal ACHN cancer lines harboring deleterious TET2 and nonsynonymous DNMT3A mutations compared to 13 lines without such mutation pattern ( P = 0.007). The treatment upregulated p21 and induced cell cycle arrest in NCI-H23 cells, and dramatically inhibited their xenograft tumor growth versus wildtype models. T-dCyd administrations led to a significant p21 increase and near eradication of tumor cells in the double-mutant xenografts by histological evaluation. TET2/DNMT3A was co-mutated in human lung, breast, skin and kidney cancers and frequently in angioimmunoblastic and peripheral T cell lymphomas and several types of leukemia.
Conclusions
Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies.
... We next compared PP-020 treated cells to cells engaged in apoptosis by staurosporine (STS) treatment ( Figure 2C). We monitored cells by western blot analysis for the Poly (ADP-ribose) polymerase (PARP) cleavage product, which is present in apoptotic cells [14]. STS treated cells revealed a PARP cleavage product whereas no signals were observed for PP-020 treated cells or other treatments. ...
INTRODUCTION: Plant species within the prairie ecological zone of Canada are a source of natural products with important bio-activities. Investigation of these plants and the secondary metabolites that they
produce will provide insight into their biology, and identify sources of natural products that may become new medicines or scientific tools.
METHODS: We investigated a G1 phase arrest activity in extracts from the prairie plant, Thermopsis rhombifolia (Buffalo bean) by biology-guided fractionation and isolated luteolin. Cell based assays and
CETSA were used to identify a cyclin-dependent kinase 9 inhibitory activity.
RESULTS AND DISCUSSION: Luteolin treated cells showed decreased phosphorylation of the carboxy terminal domain of RNA polymerase II, and low levels of Mcl-1. Plant extracts or luteolin inhibited Cdk9 (cyclin dependent kinase) in tests in vitro, stabilized Cdk9 as determined by the cellular thermal shift assay (CETSA), and arrested cells in the G1 phase of the cell cycle.
CONCLUSIONS: Luteolin joins an increasing number of flavonoid inhibitors that make convenient cell biology tools and contribute to our understanding of natural product biology in plants.
... [9,46] BRCA1 = ¬CYCD1 CYCLIN D1/Cdk4 complex inhibits BRCA1 by phopshorylation [22] BCL-2 = AKT AKT activates BCL-2 by phosphorylation of Bad (not shown) consequently releasing BCL-2 inhibition by Bad [7] BAX = ¬BCL-2 ∧ TP53 BAX gene transcription is directly activated by TP53 and its translocation to its active site (mitochondria) is blocked by BCL-2. [47,48] CYCD1 = (¬GSK3β ∧ ERK1/2) ∨(¬BRCA1 ∧ PARP1) CYCLIN D1 degradation is regulated both dependently and independently of GSK3 levels (OR), BRCA1 provokes cell cycle arrest at the G1/S transition checkpoint, PARP inhibition induces cell cycle arrest suggesting that PARP activates cell cycle transitions [37,34,14,1] Table 2. Detailed molecular mechanisms driving the Boolean network construction ...
A major challenge in cancer research is to determine the genetic mutations causing the cancerous phenotype of cells and conversely, the actions of drugs initiating programmed cell death in cancer cells. However, such a challenge is compounded by the complexity of the genotype-phenotype relationship and therefore, requires to relate the molecular effects of mutations and drugs to their consequences on cellular phenotypes. Discovering these complex relationships is at the root of new molecular drug targets discovery and cancer etiology investigation. In their elucidation, computational methods play a major role for the inference of the molecular causal actions from molecular and biological networks data analysis. In this article, we propose a theoretical framework where mutations and drug actions are seen as topological perturbations/actions on molecular networks inducing cell phenotype reprogramming. The framework is based on Boolean control networks where the topological network actions are modelled by control parameters. We present a new algorithm using abductive reasoning principles inferring the minimal causal topological actions leading to an expected behavior at stable state. The framework is validated on a model of network regulating the proliferation/apoptosis switch in breast cancer by automatically discovering driver genes and finding drug targets.
... Thus, it is Ivyspring International Publisher widely used as a surrogate marker of DSBs. Importantly, γH2AX can be induced upon exposure to ionizing irradiation and some chemotherapy agents [8,9], and has been shown to play a role in DNA damage response signaling and initiate the repair of DSBs [10]. In addition, constitutive expression of γH2AX was associated with short telomere and BRACness status [11]. ...
γH2AX plays a role in DNA damage response signaling and facilitates the repair of DNA double strand breaks. However, it remains unknown whether constitutive tumor γH2AX expression is associated with treatment outcome in patients. γH2AX status was detected in primary tumors from 24% of 826 patients with stage I, II and III breast cancer by immunohistochemistry; overall survival was analyzed by Kaplan-Meier method. At median follow-up of 176 months (range 13 - 282 months), we found substantial survival heterogeneity in γH2AX-positive patients (P=0.002) among uniform treatment groups including radiation or endocrine therapy alone and no-treatment, as well as chemotherapy alone (being worst), in contrast to γH2AX-negative patients (P=0.2). In the chemotherapy group (n=118), median survival was 63 months (95% confidence interval [CI], 29 - 83) in patients with γH2AX-positive tumors compared with 170 months (95% CI 94 - 235) in those with γH2AX-negative tumors (P=0.0017). γH2AX remained a poor prognosis factor in the group by multivariable analysis (adjusted hazard ratio 2.12, P=0.009). Our data demonstrate that constitutive γH2AX positivity is significantly associated with survival heterogeneity in patients among uniform treatment groups, and its expression at diagnosis independently predicts poor chemotherapy outcome in breast cancer.
... [2][3][4][5] Other DDR pathway molecules, such as ataxia telangiectasia mutated (ATM), breast cancer gene (BRCA), and p53, also affect the functional directions of PARP and PAR; therefore, it is important to analyze and attempt to modulate the complex connections among those proteins in the context of cancer treatment. [6][7][8] PARP inhibitors currently hold the limelight in the field of cancer treatment, particularly as monotherapies or in combination with conventional chemotherapeutics for the treatment of BRCA 1/2-mutated, HR-deficient breast, ovarian, and prostate cancers. [9][10][11][12][13] Recently, a phase II clinical trial of olaparib, a well-known PARP inhibitor, combined with paclitaxel in patients with non-BRCA gene-mutated recurrent stomach cancer yielded positive results, suggesting the potential for the extended application of PARP inhibitors. ...
... 25 In contrast, another study demonstrated that PARP inhibitor-induced DDR and cell death could be activated in both p53-dependent and -independent manners after delivering a DNA damage signal to HR-proficient cancers. 6 In the present study, p53 was activated after olaparib treatment mainly in olaparib-resistant HNC cells, suggesting that olaparib-mediated p53 activation in those cells might have led to DDR and the cell survival pathway. Conversely, p53 activation was also observed in olaparib-sensitive HN9-cisR cells along with strong PAR expression and relatively weak NF-kB expression. ...
Poly (ADP-ribose) polymerase (PARP) is a key molecule in the DNA damage response (DDR), which is a major target of both chemotherapies and radiotherapies. PARP inhibitors therefore comprise a promising class of anticancer therapeutics. In this study, we evaluated the efficacy of the PARP inhibitor olaparib, and also sought to identify the mechanism and predictive marker associated with olaparib sensitivity in head and neck cancer (HNC) cells. A total of 15 HNC cell lines, including AMC HNC cells, were tested. AMC-HN3 and HN4 exhibited stronger responses to olaparib. Among cisplatin-resistant cell lines, only AMC HN9-cisR cells were significantly suppressed by olaparib. We found that basal poly (ADP-ribose) (PAR) levels, but not PARP-1 levels, correlated with olaparib sensitivity. AMC-HN3 and HN4 cells exhibited higher basal levels of NF-κB that decreased significantly after olaparib treatment. In contrast, apoptotic proteins were intrinsically expressed in AMC-HN9-cisR cells. As interference with p53 expression led to NF-κB reactivation, we concluded that elevated basal PAR and NF-κB levels are predictive of olaparib responsiveness in HNC cells; in addition, olaparib inhibits HNC cells via PAR–p53–NF-κB interactions.
... • PARP is known to interfere with p53 function [16,24] by the inhibition of its expression; ...
... • PARP inhibition induces cell cycle arrest suggesting that PARP activates cell cycle transitions [24] which is interpreted as an activation of Cyclin D1 by PARP; ...
Complex diseases such as cancer result from the combined actions of genetic perturbations whose characterization is crucial to determine the healing treatment. The challenge of therapy discovery focuses on the identification of the causal mechanisms underlying the genotype-phenotype relationships. In this undertaking , networks provide suitable representations to model molecular interactions and enable the analysis of the effect of multiple molecular perturbations on the cell system behaviour. Although network-based analysis was announced as a key milestone for drug discovery, the challenge remains daunting. A main issue is to properly qualify the actions of diseases on networks and their dynamical effects to discover the appropriate targets for drugs. In this article, we propose a new computational method for network action inference using Boolean networks to model the dynamics of biological networks and where disease/drug actions are represented as arc additions and deletions. Based on abductive reasoning, the method finds the actions that provide the best parsimonious explanation for shifting the cell from a diseased state to a healed state. The method was applied to retrieve the necessary drug actions in the case of synthetic lethality for Breast Cancer.
... BRCA is also involved in cell cycle arrest at the G1/S checkpoint (Mullan et al., 2006;Deng, 2006); this mechanism is modelled by an inhibition of CycD1 by BRCA. Finally, PARP inhibition induces cell cycle arrest and enhances cell death in a p53dependent manner (Nguyen et al., 2011). This is modelled as PARP activation of Cyclin D1 and PARP inhibition of p53. ...
