TOPBP1

Gene Summary

Gene:TOPBP1; DNA topoisomerase II binding protein 1
Aliases: Dpb11, TOP2BP1
Location:3q22.1
Summary:This gene encodes a binding protein which interacts with the C-terminal region of topoisomerase II beta. This interaction suggests a supportive role for this protein in the catalytic reactions of topoisomerase II beta through transient breakages of DNA strands. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA topoisomerase 2-binding protein 1
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 02 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Intracellular Signaling Peptides and Proteins
  • Cancer Gene Expression Regulation
  • BRCA1 Protein
  • Dose-Response Relationship, Drug
  • DNA Damage
  • Western Blotting
  • DNA-Binding Proteins
  • Ubiquitin-Protein Ligases
  • Missense Mutation
  • Piperazines
  • Phosphorylation
  • BRCA2 Protein
  • Phthalazines
  • Chromosome 3
  • Mutation
  • Carrier Proteins
  • Genetic Predisposition
  • Breast Cancer
  • Messenger RNA
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Colorectal Cancer
  • Tumor Suppressor p53-Binding Protein 1
  • p53 Protein
  • Case-Control Studies
  • Cell Cycle Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Signal Transduction
  • Cell Cycle
  • Lung Cancer
  • MRE11 Homologue Protein
  • Nuclear Proteins
  • Risk Factors
  • Gene Expression Profiling
  • Genotype
  • Young Adult
  • DNA Repair
  • Poly(ADP-ribose) Polymerases
  • Ovarian Cancer
  • Single Nucleotide Polymorphism
  • Ubiquitin Thiolesterase
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TOPBP1 (cancer-related)

Hong S, Xu J, Li Y, et al.
Topoisomerase IIβ-binding protein 1 activates expression of E2F1 and p73 in HPV-positive cells for genome amplification upon epithelial differentiation.
Oncogene. 2019; 38(17):3274-3287 [PubMed] Free Access to Full Article Related Publications
High-risk human papillomaviruses (HPVs) constitutively activate ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) DNA damage repair pathways for viral genome amplification. HPVs activate these pathways through the immune regulator STAT-5. For the ATR pathway, STAT-5 increases expression of the topoisomerase IIβ-binding protein 1 (TopBP1), a scaffold protein that binds ATR and recruits it to sites of DNA damage. TopBP1 also acts as a transcriptional regulator, and we investigated how this activity influenced the HPV life cycle. We determined that TopBP1 levels are increased in cervical intraepithelial neoplasias as well as cervical carcinomas, consistent with studies in HPV-positive cell lines. Suppression of TopBP1 by shRNAs impairs HPV genome amplification and activation of the ATR pathway but does not affect the total levels of ATR and CHK1. In contrast, knockdown reduces the expression of other DNA damage factors such as RAD51 and Mre11 but not BRCA2 or NBS1. Interestingly, TopBP1 positively regulates the expression of E2F1, a TopBP1-binding partner, and p73 in HPV-positive cells in contrast to its effects in other cell types. TopBP1 transcriptional activity is regulated by AKT, and treatment with AKT inhibitors suppresses expression of E2F1 and p73 without interfering with ATR signaling. Importantly, the levels of p73 are elevated in HPV-positive cells and its knockdown impairs HPV genome amplification. This demonstrates that p73, like p63 and p53, is an important regulator of the HPV life cycle that is controlled by the transcriptional activating properties of the multifunctional TopBP1 protein.

Karakashev S, Zhu H, Yokoyama Y, et al.
BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer.
Cell Rep. 2017; 21(12):3398-3405 [PubMed] Free Access to Full Article Related Publications
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

Zhang W, Liu B, Wu W, et al.
Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer.
Clin Cancer Res. 2018; 24(3):696-707 [PubMed] Free Access to Full Article Related Publications

Kang DW, Lee BH, Suh YA, et al.
Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling.
Clin Cancer Res. 2017; 23(23):7340-7350 [PubMed] Related Publications

Lv Y, Liu R, Xie S, et al.
Calcein-acetoxymethy ester enhances the antitumor effects of doxorubicin in nonsmall cell lung cancer by regulating the TopBP1/p53RR pathway.
Anticancer Drugs. 2017; 28(8):861-868 [PubMed] Related Publications
Calcein acetoxymethyl ester (calcein-AM) treatment has been reported to exert antitumor effects in certain cancer cells; however, the detailed mechanism of action of calcein-AM in cancers remains unclear, especially in nonsmall cell lung cancer (NSCLC). This study focused on the function and mechanism of action of calcein-AM in NSCLC. We used cell viability assays, western blotting, and EdU proliferation assay combined with calcein-AM treatment or siRNA interference to investigate the role of topoisomerase IIβ binding protein 1 (TopBP1) and p53 in NSCLC chemotherapy. We found that calcein-AM has antitumor effects in lung cancer and enhances the antitumor effects of doxorubicin in NSCLC. Furthermore, we found that TopBP1, which we previously showed was involved in doxorubicin resistance through upregulation of aberrant p53, was involved in calcein-AM-mediated increased doxorubicin sensitivity. Doxorubicin upregulated the expression of aberrant p53. Calcein-AM repressed the expression of TopBP1, which resulted in reduced expression of aberrant p53 and disrupted the antiapoptotic activity mediated by the TopBP1/mutp53 pathway in NSCLC. Together, our findings show that calcein-AM, the cell-permeable derivative of calcein, exerts significant antitumor effects in NSCLC, and can enhance the antitumor effect of doxorubicin by regulating the TopBP1/mutp53 pathway. These findings provide novel insight into lung cancer treatment.

Karanika S, Karantanos T, Li L, et al.
Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling.
Cell Rep. 2017; 18(8):1970-1981 [PubMed] Free Access to Full Article Related Publications
Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ- and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications, since they introduce a therapeutic strategy for AR-positive, metastatic, castration-resistant PCa, regardless of p53 status, through targeting AR-CDC6-ATR-Chk1 signaling.

Kang DW, Lee SW, Hwang WC, et al.
Phospholipase D1 Acts through Akt/TopBP1 and RB1 to Regulate the E2F1-Dependent Apoptotic Program in Cancer Cells.
Cancer Res. 2017; 77(1):142-152 [PubMed] Related Publications
The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the Apc

Starska K, Forma E, Nowacka-Zawisza M, et al.
The c.*229C > T gene polymorphism in 3'UTR region of the topoisomerase IIβ binding protein 1 gene and LOH in BRCA1/2 regions and their effect on the risk and progression of human laryngeal carcinoma.
Tumour Biol. 2016; 37(4):4541-57 [PubMed] Related Publications
Topoisomerase IIβ binding protein 1 (TopBP1), a multiple-BRCT-domain, protein plays crucial roles in chromosome replication, DNA damage repair, apoptosis, and cell cycle checkpoint signalling. The aim of this study was to identify five SNPs at loci potentially located in the 3'UTR region of the TopBP1 gene (rs185903567, rs116645643, rs115160714, rs116195487, rs112843513), their relationship with the risk of squamous cell laryngeal cancer (SCLC), tumor invasiveness, and prognosis. Genotyping was performed in 323 genetically unrelated individuals with SCLC and 418 randomly selected healthy volunteers. Allele-specific TopBP1 mRNA and protein expressions were determined by using real-time PCR and Western blotting techniques, respectively. LOH in BRCA1/BRCA2 was determined by using microsatellite markers. Compared to homozygous common allele carriers, heterozygosity for the T variant was associated with increased risk of SCLC (adjusted odds ratio [OR] = 9.83, 95 % confidence interval [CI]: 3.12-22.16, p dominant < 0.0001). The presence of risk allele at rs115160714 TopBP1 determined a higher incidence of nodal metastases (OR = 7.98, 95 % CI: 3.94-16.00, p = 0.001) and higher tumor grade (OR = 6.48, 95 % CI: 0.86-48.01, p = 0.03). The heterozygotes displayed diffuse tumor growth with no distinct borderline (OR = 3.10, 95 % Cl: 0.92-10.62, p = 0.049) and higher depth of invasion (OR = 2.66, 95 % Cl: 0.78-9.03, p = 0.04). Relationships were also identified between TopBP1 mRNA/protein expression and overall survival (p < 0.0001). The incidence of LOH in BRCA1/BRCA2 was significantly related to higher tumor grade and TFG (p < 0.05). The results of this study suggest that rs115160714 TopBP1 may be a genetic marker of etiology and progression in laryngeal cancer.

Beumer JH, Fu KY, Anyang BN, et al.
Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma : ATM, ATR and FA in lung carcinoma.
BMC Cancer. 2015; 15:649 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas.
METHODS: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes.
RESULTS: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54 T, 201 T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201 T and 239 T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines.
CONCLUSIONS: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor UCN-01 were observed and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors.

Wang LR, He LJ, Wang Y, et al.
Correlation between BRCA1 and TopBP1 protein expression and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy.
Cancer Chemother Pharmacol. 2015; 76(1):163-70 [PubMed] Related Publications
PURPOSE: To investigate the correlation between protein expression of breast cancer susceptibility gene 1 (BRCA1) and topoisomerase IIβ-binding protein 1 (TopBP1) and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy.
METHODS: Immunohistochemical staining was conducted to detect the protein expression of BRCA1 and TopBP1 in 101 cases of NSCLC and to correlate these with clinical features, disease progression, and patient survival. Chi-square test (χ (2)-test) was used to evaluate categorical variables. Spearman's rank order correlation was used to analyze continuous variables. Overall survival rate of NSCLC patients was analyzed by Kaplan-Meier survival curve and log-rank test. Relevant factors affecting the survival of patients with advanced NSCLC were analyzed by COX proportional hazards regression model.
RESULTS: A total of 101 NSCLC patients were included in the present study. In tumor tissue specimens, positive expression rates of BRCA1 and TopBP1 proteins were 51.5 and 57.4 %, respectively. A significant correlation between the positive expression of BRCA1 and the positive expression of TopBP1 was observed (P < 0.001, r = 0.326). No significant correlation between BRCA1/TopBP1 and age, gender, smoking status, performance status score, pathohistological type, or clinical stage was detected (P > 0.05). During the follow-up period, 65 patients died, and 86 patients showed progression at the end of the study. The survival rate of patients with negative BRCA1 protein expression was higher than that in patients with positive BRCA1 protein expression [median overall survival (OS) 34 vs. 21 months, HR 1.913, 95 % CI 1.161-3.150, P = 0.011]. Similarly, the survival rate of patients with negative TopBP1 expression was higher than that in patients with positive TopBP1 (median OS 36 vs. 23 months, HR 1.931, 95 % CI 1.157-3.224, P = 0.012). No significant correlation between protein expression of BRCA1 or TopBP1 with NSCLC disease progression was observed (P > 0.05).
CONCLUSIONS: The present study indicates NSCLC patients with negative BRCA1 and TopBP1 expression showed better prognosis than those with positive protein expression.

Smith-Roe SL, Nakamura J, Holley D, et al.
SWI/SNF complexes are required for full activation of the DNA-damage response.
Oncotarget. 2015; 6(2):732-45 [PubMed] Free Access to Full Article Related Publications
SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated in ~20% of all human primary tumors. Yet our knowledge of their tumor-suppressor mechanism is limited. To investigate the role of SWI/SNF complexes in the DNA-damage response (DDR), we used shRNAs to deplete BRG1 and BRM and then exposed these cells to a panel of 6 genotoxic agents. Compared to controls, the shRNA knockdown cells were hypersensitive to certain genotoxic agents that cause double-strand breaks (DSBs) associated with stalled/collapsed replication forks but not to ionizing radiation-induced DSBs that arise independently of DNA replication. These findings were supported by our analysis of DDR kinases, which demonstrated a more prominent role for SWI/SNF in the activation of the ATR-Chk1 pathway than the ATM-Chk2 pathway. Surprisingly, γH2AX induction was attenuated in shRNA knockdown cells exposed to a topoisomerase II inhibitor (etoposide) but not to other genotoxic agents including IR. However, this finding is compatible with recent studies linking SWI/SNF with TOP2A and TOP2BP1. Depletion of BRG1 and BRM did not result in genomic instability in a tumor-derived cell line but did result in nucleoplasmic bridges in normal human fibroblasts. Taken together, these results suggest that SWI/SNF tumor-suppressor activity involves a role in the DDR to attenuate replicative stress and genomic instability. These results may also help to inform the selection of chemotherapeutics for tumors deficient for SWI/SNF function.

Chowdhury P, Lin GE, Liu K, et al.
Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy.
Nat Commun. 2014; 5:5476 [PubMed] Free Access to Full Article Related Publications
The progression of many solid tumours is driven by deregulation of multiple common pathways, particularly Rb, PI(3)K/Akt and p53. Prior studies identified TopBP1 as a key mediator for the oncogenic gain-of-function activities of mutant p53 (mutp53) in cancer. In Akt-hyperactive cancer, TopBP1 forms oligomers and represses E2F1-dependent apoptosis. Here we perform a molecular docking screening and identify a lead compound, calcein, capable of blocking TopBP1 oligomerization and p53 binding, resulting in re-activation of E2F1-dependent apoptosis and blockade of mutp53 gain-of-function. Calcein AM, the cell-permeable derivative of calcein, shows significant antitumour activity in a wide spectrum of cultured cancer cells harbouring high TopBP1 levels. These biochemical findings are recapitulated in breast cancer xenograft models. Thus, our study provides proof-of-concept evidence for targeting TopBP1, a convergent point of multiple pathways, as a cancer therapy.

Choi SH, Yang H, Lee SH, et al.
TopBP1 and Claspin contribute to the radioresistance of lung cancer brain metastases.
Mol Cancer. 2014; 13:211 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Radiation therapy is one of the most effective therapeutic tools for brain metastasis. However, it is inevitable that some cancer cells become resistant to radiation. This study is focused on the identification of genes associated with radioresistance in metastatic brain tumor from lung cancer and the functional examination of the selected genes with regards to altered sensitivity of cancer cells to radiation.
METHODS: After establishing radioresistant cells from the xenograft model, we explored the significant transcriptional changes by performing DNA microarray profiling. Functional analyses in vitro and in vivo performed to validate the gene responsible for radioresistance.
RESULTS: Transcriptional changes induced by radiation therapy are much more extensive in H460 cells than in PC14PE6 cells. The expression levels of TopBP1 and Claspin were increased in the cancer cells that survived radiation therapy. Depletion of TopBP1 or Claspin using shRNA showed an enhancement of sensitivity to radiation in radioresistant lung cancer cells (PC14PE6). Moreover, increased levels of TopBP1 or Claspin endowed cells a higher resistance to radiation. In xenograft models, the knock-down of TopBP1 or Claspin significantly prolonged the median survival time post radiation therapy.
CONCLUSIONS: We analyzed the gene expression profiles of the radiosensitive cells and the radioresistant cells to define a set of genes that may be involved in endowing lung cancer cells radioresistance post brain metastasis. Functional analyses indicated that the expression TopBP1 and Claspin positively affects the survival of cancer cells and thus negatively the xenograft metastasis model animals in response to radiation. These results show that TopBP1 and Claspin can be potential targets for the enhanced efficacy of radiotherapy.

Li L, Chang W, Yang G, et al.
Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer.
Sci Signal. 2014; 7(326):ra47 [PubMed] Free Access to Full Article Related Publications
Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that c-Myb may supplant AR as the dominant regulator of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures including AR, MYB, and their common DDR-associated target genes positively correlated with metastasis, castration resistance, tumor recurrence, and decreased survival in PCa patients. In culture and in xenograft-bearing mice, a combination strategy involving the knockdown of MYB, BRCA1, or TOPBP1 or the abrogation of cell cycle checkpoint arrest with AZD7762, an inhibitor of the checkpoint kinase Chk1, increased the cytotoxicity of the poly[adenosine 5'-diphosphate (ADP)-ribose] polymerase (PARP) inhibitor olaparib in PCa cells. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the DDR pathway involving c-Myb, TopBP1, ataxia telangiectasia mutated- and Rad3-related (ATR), and Chk1.

Heikkinen T, Khan S, Huovari E, et al.
Evaluation of the RHINO gene for breast cancer predisposition in Finnish breast cancer families.
Breast Cancer Res Treat. 2014; 144(2):437-41 [PubMed] Related Publications
Hereditary predisposition to breast cancer is largely affected by the mutations in the genes of the DNA repair pathways. Novel genes involved in DNA repair are therefore prospective candidates also for breast cancer susceptibility genes. The RHINO (Rad9, Rad1, Hus1-interacting nuclear orphan) gene plays a central role in DNA damage response and in cell cycle regulation. RHINO interacts with Rad9-Rad1-Hus1 (9-1-1) complex and with ATR activator TopBP1, which recruit it to the site of DNA damage. We analyzed the effects of the germline variation in RHINO on breast cancer risk. We sequenced the coding region of the RHINO gene 466 index cases of Finnish breast cancer families and in 507 population controls. The genotypes of the most likely functional variant were further determined in a large dataset of 2,944 cases and 1,976 controls. We analyzed the common variation of the RHINO locus and determined the haplotypes using five SNPs in 1,531 cases and 1,233 controls. We identified seven variants including four missense variations, a 5' UTR variant, a silent variant, and a nonsense variant c.250C>T, R84X (rs140887418). All variants were also present in control individuals with frequencies close to those of the cases (P > 0.05). The c.250C>T variant was present in 12 breast cancer patients (0.4 %) and of 16 controls (0.8 %) with the difference not statistically significant (OR = 0.50, 95 %CI: 0.24-1.06, P = 0.066). The haplotype frequencies did not differ in cases and controls (P = 0.59). Germline variation in the RHINO gene is unlikely to influence inherited susceptibility to breast cancer.

Forma E, Wójcik-Krowiranda K, Jóźwiak P, et al.
Topoisomerase IIβ binding protein 1 c.*229C>T (rs115160714) gene polymorphism and endometrial cancer risk.
Pathol Oncol Res. 2014; 20(3):597-602 [PubMed] Free Access to Full Article Related Publications
TopBP1 (topoisomerase IIβ binding protein 1) protein is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. In this study we investigated whether alterations in the TopBP1 gene can influence the risk of endometrial cancer. We examined the association between five single nucleotide polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 3'UTR region of the TopBP1 gene and endometrial cancer risk as well as allele-specific gene expression. One hundred twenty-one endometrial cancer patients were genotyped for these SNPs. Allele-specific TopBP1 mRNA and protein expressions were determined by real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with endometrial cancer. Compared to homozygous common allele carriers, heterozygous for the T variant had significantly increased risk of endometrial cancer [adjusted odds ratio (OR) = 5.59, 95 % confidence interval (CI): 1.96-15.91, p = 0.0003]. Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT genotype. There was a significant association between the rs115160714 and tumor grade and FIGO classification. Most carriers of minor allele had a high grade tumors (G3) classified as FIGO III/IV. The results of our study raise a possibility that a genetic variation of TopBP1 may be implicated in the etiology of endometrial cancer.

Jang JH, Cotterchio M, Borgida A, et al.
Interaction of polymorphisms in mitotic regulator genes with cigarette smoking and pancreatic cancer risk.
Mol Carcinog. 2013; 52 Suppl 1:E103-9 [PubMed] Free Access to Full Article Related Publications
Mitotic regulator genes have been associated with several cancers, however little is known about their possible association with pancreatic cancer. Smoking and family history are the strongest risk factors for this highly fatal disease. The main purpose of this study was to determine if polymorphisms of mitotic regulator genes are associated with pancreatic cancer and whether they modify the association between cigarette smoking and pancreatic cancer risk. A population-based case-control study was conducted in Ontario with 455 pathology-confirmed pancreatic cancer cases and 893 controls. Cigarette smoking history was collected using questionnaires and DNA obtained from blood samples. Genotypes were determined by mass-spectrometry. Odds ratio estimates were obtained using multivariate logistic regression. Interactions between genetic variant and smoking were assessed using stratified analyses and the likelihood ratio statistic (significance P < 0.05). Variants of MCPH1, FYN, APC, PRKCA, NIN, TopBP1, RIPK1, and SNW1 were not independently associated with pancreatic cancer risk. A significant interaction was observed between pack-years and MCPH1-2550-C > T (P = 0.02). Compared to never smokers, individuals with 10-27 pack-years and MCPH1-2550-CC genotype were at increased risk for pancreatic cancer (MVOR = 2.49, 95% confidence interval [95% CI]: 1.55, 4.00) as were those with >27 pack-years and MCPH1-2550-TC genotype (MVOR = 2.42, 95% CI: 1.45, 4.05). A significant interaction was observed between smoking status and TopBP1-3257-A > G (P = 0.04) using a dominant model. Current smokers with the TopBP1-3257 A allele were at increased risk for pancreatic cancer (MVOR = 2.55, 95% CI: 1.77, 3.67). MCPH1-2550-C > T and TopBP1-3257-A > G modify the association between smoking and pancreatic cancer. These findings provide insights into the potential molecular mechanisms behind smoking-associated pancreatic cancer.

Forma E, Brzeziańska E, Krześlak A, et al.
Association between the c.*229C>T polymorphism of the topoisomerase IIβ binding protein 1 (TopBP1) gene and breast cancer.
Mol Biol Rep. 2013; 40(5):3493-502 [PubMed] Free Access to Full Article Related Publications
Topoisomerase IIβ binding protein 1 (TopBP1) is involved in cell survival, DNA replication, DNA damage repair and cell cycle checkpoint control. The biological function of TopBP1 and its close relation with BRCA1 prompted us to investigate whether alterations in the TopBP1 gene can influence the risk of breast cancer. The aim of this study was to examine the association between five polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 3'UTR region of the TopBP1 gene and breast cancer risk as well as allele-specific gene expression. Five hundred thirty-four breast cancer patients and 556 population controls were genotyped for these SNPs. Allele-specific TopBP1 mRNA and protein expressions were determined by using real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with breast cancer. Compared to homozygous common allele carriers, heterozygous and homozygous for the T variant had significantly increased risk of breast cancer (adjusted odds ratio = 3.81, 95% confidence interval: 1.63-8.34, p = 0.001). Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT or TT genotype. There was a significant association between the rs115160714 and tumor grade and stage. Most carriers of minor allele had a high grade (G3) tumors classified as T2-T4N1M0. Our study raises a possibility that a genetic variation of TopBP1 may be implicated in the etiology of breast cancer.

Forma E, Krzeslak A, Bernaciak M, et al.
Expression of TopBP1 in hereditary breast cancer.
Mol Biol Rep. 2012; 39(7):7795-804 [PubMed] Free Access to Full Article Related Publications
TopBP1 protein displays structural as well as functional similarities to BRCA1 and is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. Aberrant expression of TopBP1 may lead to genomic instability and can have pathological consequences. In this study we aimed to investigate expression of TopBP1 gene at mRNA and protein level in hereditary breast cancer. Real-time quantitative PCR was performed in 127 breast cancer samples. Expression of TopBP1 mRNA in lobular carcinoma was significantly lower compared with ductal carcinoma (p < 0.05). The level of TopBP1 mRNA appeared to be lower in poorly differentiated (III grade) hereditary breast cancer in comparison with moderately (II grade) and well-differentiated cancer (I grade) (p < 0.05 and p < 0.001 respectively). We analyzed TopBP1 protein expression using immunohistochemistry and Western blot techniques. Expression of TopBP1 protein was found to be significantly increased in poorly differentiated breast cancer (III grade) (p < 0.05). The percentage of samples with cytoplasmic apart from nuclear staining increased with increasing histological grade. There was no significant association between level and intracellular localization of TopBP1 protein in hereditary breast cancer and other clinicopathological parameters such as estrogen and progesterone receptors status, appearance of metastasis in the axillary lymph nodes and type of cancer. Our data suggest that decreased level of TopBP1 mRNA and increased level of TopBP1 protein might be associated with progression of hereditary breast cancer.

Liu K, Ling S, Lin WC
TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73.
Mol Cell Biol. 2011; 31(22):4464-81 [PubMed] Free Access to Full Article Related Publications
Nearly half of human cancers harbor p53 mutations, which can promote cancerous growth, metastasis, and resistance to therapy. The gain of function of mutant p53 is partly mediated by its ability to form a complex with NF-Y or p63/p73. Here, we demonstrate that TopBP1 mediates these activities in cancer, and we provide both in vitro and in vivo evidence to support its role. We show that TopBP1 interacts with p53 hot spot mutants and NF-YA and promotes mutant p53 and p300 recruitment to NF-Y target gene promoters. TopBP1 also facilitates mutant p53 interaction with and inhibition of the transcriptional activities of p63/p73. Depletion of TopBP1 in mutant p53 cancer cells leads to downregulation of NF-Y target genes cyclin A and Cdk1 and upregulation of p63/p73 target genes such as Bax and Noxa. Mutant p53-mediated resistance to chemotherapeutic agents depends on TopBP1. The growth-promoting activity of mutant p53 in a xenograft model also requires TopBP1. Thus, TopBP1 mediates mutant p53 gain of function in cancer. Since TopBP1 is often overexpressed in cancer cells and is recruited to cooperate with mutant p53 for tumor progression, TopBP1/mutant p53 interaction may be a new therapeutic target in cancer.

Abulí A, Fernández-Rozadilla C, Giráldez MD, et al.
A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22.
Br J Cancer. 2011; 105(6):870-5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24.
METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24.
RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk.
CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

Rebbeck TR, Mitra N, Domchek SM, et al.
Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes.
Cancer Res. 2011; 71(17):5792-805 [PubMed] Free Access to Full Article Related Publications
Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

Kim KH, Yoo HY, Joo KM, et al.
Time-course analysis of DNA damage response-related genes after in vitro radiation in H460 and H1229 lung cancer cell lines.
Exp Mol Med. 2011; 43(7):419-26 [PubMed] Free Access to Full Article Related Publications
Radiation is the most useful treatment modality for cancer patients. It initiates a series of signal cascades such as DNA damage response (DDR) signaling for repairing damaged DNA, arresting the cell cycle, and inducing cell death. Until now, few genes have been found to be regulated by radiation, which explains the molecular mechanisms of cellular responses to radiation. Although the transcriptional changes caused by radiation have been widely investigated, little is known about the direct evidence for the transcriptional control of DDR-related genes. Here, we examined the radiosensitivity of two non-small cell lung cancer cell lines (H460 and H1299), which have different p53 status. We monitored the time-dependent changes of 24 DDR-related gene expressions via microarray analysis. Based on the basal expression levels and temporal patterns, we further classified 24 DDR-related genes into four subgroups. Then, we also addressed the protein levels of several DDR-related genes such as TopBP1, Chk1 and Chk2, confirming the results of microarray analysis. Together, these results indicate that the expression patterns of DDR-related genes are associated with radiosensitivity and with the p53 statuses of H460 and H1299, which adds to the understanding of the complex biological responses to radiation.

Kim YR, Chung NG, Kang MR, et al.
Novel somatic frameshift mutations of genes related to cell cycle and DNA damage response in gastric and colorectal cancers with microsatellite instability.
Tumori. 2010 Nov-Dec; 96(6):1004-9 [PubMed] Related Publications
AIMS AND BACKGROUND: Microsatellite instability (MSI) in sporadic gastric cancer (GC) and colorectal cancer (CRC) causes frameshift mutations in gene sequences that contribute to cancer pathogenesis. Many mutations have already been identified in these two cancer types, but some are still undiscovered.
METHODS: We analyzed seven genes (cell cycle control and DNA damage signaling/repair-related genes) with seven or more mononucleotide repeats in 30 GC samples with high MSI (MSI-H), 15 GC samples with low MSI (MSI-L), 45 GC samples that were microsatellite stable (MSS), 33 CRC samples with MSI-H, 15 CRC samples with MSI-L, and 45 CRC samples that were MSS. Single-strand conformation polymorphism (SSCP) and DNA sequencing were used for the analysis.
RESULTS: We found somatic frameshit mutations of the KNTC1 (6.7% GC, 12.1% CRC), ZC3H13 (3.3% GC, 15.2% CRC), CENPH (6.7% GC), TOPBP1 (3.0% CRC), NDCO80 (3.0% CRC), RIF1 (6.7% GC), and NBS1 (3.3% GC, 3.0% CRC) genes in the cancers with MSI-H. Mutations were detected in MSI-H, but not in MSI-L or MSS samples.
CONCLUSIONS: Novel frameshift mutations occurred in seven genes in GC and CRC with MSI-H. The results of our study suggest that the mutations might contribute to the development of GC and CRC with MSI by deregulation of the cell cycle and DNA damage signaling/repair.

Blaut MA, Bogdanova NV, Bremer M, et al.
TOPBP1 missense variant Arg309Cys and breast cancer in a German hospital-based case-control study.
J Negat Results Biomed. 2010; 9:9 [PubMed] Free Access to Full Article Related Publications
The DNA double strand break repair gene TOPBP1 has been suggested as a breast cancer susceptibility gene and a missense variant Arg309Cys was observed at elevated frequency in familial breast cancer cases compared to healthy controls from Finland. We found the Arg309Cys allele at a 13% carrier frequency in a hospital-based series of 1064 German breast cancer patients and at a 14% carrier frequency in 1014 population controls (OR 0.89, 95%CI 0.69-1.15; p = 0.4). Arg309Cys carriers were not enriched among patients with a family history of breast cancer (OR = 0.87, 95%CI 0.53-1.43, p = 0.6) and were slightly underrepresented in patients with bilateral disease (OR = 0.49, 95%CI = 0.24-0.99; p = 0.047). In the latter group, the mean age at diagnosis was 62 years in carriers and 54 years in non-carriers (p = 0.004). We conclude that there is no evidence for the TOPBP1*Arg309Cys variant to confer an increased risk for breast cancer in the German population.

Cescutti R, Negrini S, Kohzaki M, Halazonetis TD
TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint.
EMBO J. 2010; 29(21):3723-32 [PubMed] Free Access to Full Article Related Publications
TopBP1 is a checkpoint protein that colocalizes with ATR at sites of DNA replication stress. In this study, we show that TopBP1 also colocalizes with 53BP1 at sites of DNA double-strand breaks (DSBs), but only in the G1-phase of the cell cycle. Recruitment of TopBP1 to sites of DNA replication stress was dependent on BRCT domains 1-2 and 7-8, whereas recruitment to sites of DNA DSBs was dependent on BRCT domains 1-2 and 4-5. The BRCT domains 4-5 interacted with 53BP1 and recruitment of TopBP1 to sites of DNA DSBs in G1 was dependent on 53BP1. As TopBP1 contains a domain important for ATR activation, we examined whether it contributes to the G1 cell cycle checkpoint. By monitoring the entry of irradiated G1 cells into S-phase, we observed a checkpoint defect after siRNA-mediated depletion of TopBP1, 53BP1 or ATM. Thus, TopBP1 may mediate the checkpoint function of 53BP1 in G1.

Rebbeck TR, Mitra N, Domchek SM, et al.
Modification of ovarian cancer risk by BRCA1/2-interacting genes in a multicenter cohort of BRCA1/2 mutation carriers.
Cancer Res. 2009; 69(14):5801-10 [PubMed] Free Access to Full Article Related Publications
Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (P(corr)) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (P(corr) = 0.007). At NBS1, we observed a P(corr) = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (P(corr) = 0.044) and BARD1 (P(corr) = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (P(corr) = 0.011). At MRE11, we observed a significant haplotype association (P(corr) = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (P(corr) = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations.

Liu K, Bellam N, Lin HY, et al.
Regulation of p53 by TopBP1: a potential mechanism for p53 inactivation in cancer.
Mol Cell Biol. 2009; 29(10):2673-93 [PubMed] Free Access to Full Article Related Publications
Proper control of the G(1)/S checkpoint is essential for normal proliferation. The activity of p53 must be kept at a very low level under unstressed conditions to allow growth. Here we provide evidence supporting a crucial role for TopBP1 in actively repressing p53. Depletion of TopBP1 upregulates p53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis. The regulation is mediated by an interaction between the seventh and eighth BRCT domains of TopBP1 and the DNA-binding domain of p53, leading to inhibition of p53 promoter binding activity. Importantly, TopBP1 overexpression is found in 46 of 79 primary breast cancer tissues and is associated with high tumor grade and shorter patient survival time. Overexpression of TopBP1 to a level comparable to that seen in breast tumors leads to inhibition of p53 target gene expression and DNA damage-induced apoptosis and G(1) arrest. Thus, a physiological level of TopBP1 is essential for normal G(1)/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior.

Sellick GS, Wade R, Richards S, et al.
Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis.
Blood. 2008; 111(3):1625-33 [PubMed] Related Publications
To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P = .03), IL19 S213F (P = .001), LILRA4 P27L (P = .004), KLRC4 S29I (P = .007), and CD5 V471A (P = .002); and DNA response genes POLB P242R (P = .04) and TOPBP1 S730L (P = .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (IgV(H)) mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available.

Going JJ, Nixon C, Dornan ES, et al.
Aberrant expression of TopBP1 in breast cancer.
Histopathology. 2007; 50(4):418-24 [PubMed] Related Publications
AIMS: The TopBP1 protein includes eight BRCT domains (originally identified in BRCA1) and has homology with BRCA1 over the carboxyl terminal half of the protein. The aim of this study was to determine whether TopBP1 is aberrantly expressed in breast cancer.
METHODS AND RESULTS: Sixty-one breast carcinomas from an unselected consecutive patient cohort were studied along with 12 samples of breast tissue from cosmetic breast reduction surgery; these were analysed immunohistochemically for TopBP1 expression using a rabbit polyclonal antibody. This antibody was validated in immunoprecipitation and immunofluorescence experiments. Immunohistochemical analysis demonstrated that TopBP1 was expressed almost exclusively in the nuclei of the normal breast epithelium. However, in a significant number of breast carcinomas TopBP1 was aberrantly expressed, as it was detected in the cytoplasm and nucleus of some tumours and exclusively in the cytoplasm of others. In two out of 61 carcinomas investigated, no TopBP1 expression was detected.
CONCLUSIONS: For the first time this report demonstrates aberrant expression of the TopBP1 protein in breast carcinoma. We propose TOPBP1 as a breast cancer susceptibility gene.

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