Topoisomerase 1 activity during mitotic transcription favors the transition from mitosis to G1

Data about lipoprotein changes and their link with cardiovascular disease and atherosclerosis in systemic sclerosis (SSc) are still challenging. We aimed to evaluate serum lipid profile of patients with SSc and to identify potential relation with different disease specific characteristics (clinical, serological, inflammatory tests) in a cross-sectional study. Standard assessments comprised SSc-related parameters (disease subtype, clinical spectrum, immunological tests) and lipid metabolism (total cholesterol and fractions, triglycerides). Impaired lipid profile (low serum HDL- and high LDL-cholesterol, increased serum triglycerides, slightly modification in total cholesterol level) significantly correlated with diffuse SSc, activity (EUSTAR) and severity (MEDSGER), as well as seropositivity for specific antibodies (anti-centromere and anti-topoisomerase 1). The dyslipidemic profile might represent a pathobiological pathway for atherosclerosis in SSc.

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Topoisomerase 1 Inhibitors and Cancer Therapy

Hematology/Oncology Clinics of North America ◽

10.1016/j.hoc.2012.03.002 ◽

2012 ◽

Vol 26 (3) ◽

pp. 507-525 ◽

Cited By ~ 28

Author(s):

Julia Moukharskaya ◽

Claire Verschraegen

Keyword(s):

Cancer Therapy ◽

Topoisomerase 1

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POS0853 DECREASE IN ANTI-TOPOISOMERASE-1 ANTIBODY TITER IN PATIENTS WITH SYSTEMIC SCLEROSIS DURING LONG-TERM RITUXIMAB THERAPY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2038 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 681.1-681

Author(s):

L. Garzanova ◽

L. P. Ananyeva ◽

O. Koneva ◽

O. Desinova ◽

O. Ovsyannikova ◽

...

Keyword(s):

Systemic Sclerosis ◽

B Lymphocytes ◽

Vital Capacity ◽

Clinical Parameters ◽

Diffusion Capacity ◽

Positive Group ◽

Topoisomerase 1 ◽

The Mean

Background:Rituximab (RTX) is a new option in the treatment of systemic sclerosis (SSc) [1]. There is not enough data on changes in the level of autoantibodies and their clinical significance during RTM therapy. There are only a few reports on the higher efficiency of RTX in patients (pts) with SSc positive for anti-topoisomerase-1 antibodies (a-Topo-1), therefore the study of this issue might be interested.Objectives:To compare clinical parameters and B-lymphocytes (B-lymph) level in SSc pts depending on the presence or absence of a-Topo-1 during RTX therapy with prospective long-term follow-up.Methods:This study included 88 pts with SSc. The mean follow-up period was 26,3±10,7 months. The mean age was 47years (17-71), female-73 pts (83%), the diffuse cutaneous subset of the disease had 50 pts (57%). Symptoms of the interstitial lung disease (ILD) were observed in 70 pts (80%). The mean disease duration was 5,9±4,8 years. The cumulative mean dose of RTX was 2,9±1,1 grams. All patients received prednisone at a dose of 11,7±4,4 mg, immunosuppressants received 42% of them. There were 63 pts positive for a-Topo-1 and 25 pts - negative. The pts of the compared groups did not differ in the main demographic and clinical parameters, excepting lung involvement. In a-Topo-1 positive group 55 (87%) pts had ILD and only 15 (60%) – in a-Topo-1-negative group (p=0,02). The results at baseline and at the end of the follow up are presented in the form of mean values and changes in parameters (delta).Results:Considering the entire cohort, an improvement of almost all outcome parameters was found. When a-Topo-1 positive and a-Topo-1-negative pts were analyzed separately, we observed a significantly higher decrease in the activity score, depletion of B-lymph, an increase in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) in a-Topo-1 positive group of pts (table 1).Table 1.Changes of the main outcome parameters depending on the presence of a-Topo-1 on RTX therapy.Parametersa-Topo-1positive ptsa-Topo-1negative ptsPDelta Activity score (EScSG-AI)1,790,90,001Delta Rodnan skin score (mRSS)4,95,2NSDelta B-lymphocytes (absolute count)0,2120,1930,001Delta FVC*, %8,646,460,001Delta DLCO**, %2,860,0320,001*FVC - forced vital capacity % predicted, **DLCO - diffusion capacity for carbon monoxide % predictedThe a-Тopo-1 level decreased from 174,2±50,1 to 148,1±66,1 units/ml (p=0,0009). In this group, a-Тopo-1 became negative in 5 pts (7,9%). The disappearance of a-Topo-1 positivity was accompanied by a more pronounced decrease in mRSS (delta mRSS=7,4) and a higher depletion of B-lymph. There was a higher cumulative dose of RTX (4±1,4grams) in this 5 pts compared with the pts who sustained a-Topo-1 positivity. There was a moderate negative statistically significant correlation between the a-Topo-1 and the total dose of RTX (r=-0,298, p=0,017). A moderate negative statistically significant correlation was found between the a-Topo-1 and FVC (r=-0,322, p=0,009).Conclusion:In our study, the a-Topo-1 level significantly decreased during RTX therapy in Russian pts. The decrease in a-Topo-1 titers correlated with the total dose of RTX and was accompanied by a decrease in mRSS, disease activity index and an increase in FVC and DLCO. A higher efficacy of RTX in the a-Topo-1 positive group with prevalence of ILD was revealed, therefore a-Topo-1 positivity could be considered as a predictor of a better response to RTX therapy.References:[1]Jordan S, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis.2015;74:1188–94.Doi:10.1136/annrheumdis-2013-204522.[2]Ebata S, Yoshizaki A, et.al. Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti-topoisomerase I-positive systemic sclerosis-associated interstitial lung disease. J Dermatol.2019.Nov;46(11):1006-1013.doi:10.1111/1346-8138.15079.Disclosure of Interests:None declared

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Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration

Nature Communications ◽

10.1038/s41467-020-15794-9 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Giulia Fragola ◽

Angela M. Mabb ◽

Bonnie Taylor-Blake ◽

Jesse K. Niehaus ◽

William D. Chronister ◽

...

Keyword(s):

Genomic Instability ◽

Early Onset ◽

Topoisomerase 1 ◽

Excitatory Neurons

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The DNA damage inducible lncRNA SCAT7 regulates genomic integrity and topoisomerase 1 turnover in lung adenocarcinoma

NAR Cancer ◽

10.1093/narcan/zcab002 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Luisa Statello ◽

Mohamad M Ali ◽

Silke Reischl ◽

Sagar Mahale ◽

Subazini Thankaswamy Kosalai ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Cancer Biology ◽

Topoisomerase I ◽

Cell Cycle Checkpoints ◽

Topoisomerase 1 ◽

Damage Response ◽

Promote Cell Survival

Abstract Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.

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O18 Integrated molecular analysis of systemic sclerosis skin and blood shows significant differences between major autoantibody subgroups

Rheumatology ◽

10.1093/rheumatology/keab246.017 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Kristina E Clark ◽

Corrado Campochiaro ◽

Eszter Csomor ◽

Adam Taylor ◽

Katherine Nevin ◽

...

Keyword(s):

Gene Expression ◽

Systemic Sclerosis ◽

Whole Blood ◽

Serum Markers ◽

Differentially Expressed ◽

Longitudinal Change ◽

Beta Catenin ◽

Skin Score ◽

Topoisomerase 1 ◽

Organ Manifestations

Abstract Background/Aims The major antinuclear autoantibodies of systemic sclerosis (SSc) associate with different skin score trajectories and risk of internal organ manifestations. To elucidate molecular differences between ANA-defined subgroups, we utilised the prospective BIOPSY cohort of well-characterised SSc patients. Methods The prospectively collected BIOPSY cohort recruited 52 SSc patients (21 early dcSSc, 15 established dcSSc, 16 lcSSc) and 16 healthy controls (HC). 36 (69%) of the SSc patients are female. Mean disease duration in the early dcSSc cohort was 24 months (sd 12 months), and in established dcSSc was 11.3 years. ANA frequency in BIOPSY reflected the overall dcSSc population: anti-topoisomerase-1 (ATA) n = 14 (27%), anti-RNA pol III (ARA) n = 12 (23%) and other n = 26 (50%). Mean baseline skin score (MRSS) for early dcSSc was 21 (sd 11.2). At a group level mRSS peak was 21.9 (11.8) at 3 months and fell to 19.1(10.5) at 12 months. Serum biomarkers of ECM turnover and fibrosis were measured three monthly and genome-wide transcriptomic profiling of whole skin and whole blood performed by RNA-Seq. Statistical analysis used RStudio with ANOVA, and Tukey post-hoc test. Differential gene expression used the Bioconductor limma software, with standard thresholds for significance. Results At baseline, there were differences in soluble markers between clinical SSc sugroups and HC but not for major ANA subgroups. However, we found clear differences in early dcSSc analysed by major ANA subset for longitudinal change in serum markers of fibrosis and in whole skin gene expression, suggesting a mechanistic basis for the distinct clinical phenotypes associated with hallmark ANAs. During follow-up, significant differences were observed in HA, TIMP1, and PIIINP at 6 and 12 months (p < 0.05), with stable levels in ATA+ patients compared to progressively increased levels in the other subgroups. There were 564 significantly differentially expressed genes in skin between early dcSSc and HC. Unsupervised clustering differentiated patients with ARA and ATA positivity with early dcSSc. 54 genes were significantly differentially expressed in skin between ATA and ARA patients. Whilst 179 genes were differentially expressed in whole blood between early dcSSc compared with HC, no genes could significantly differentiate ATA from ARA. Functional analysis using HALLMARK pathway analysis identified both shared pathways associated with SSc across ANA groups (e.g. TGF beta signaling, IL6 JAK STAT3 signalling, inflammatory response), and pathways only upregulated in patients with ATA (e.g. Wnt beta catenin signaling, Notch signaling), and ARA (e.g. interferon gamma response, adipogenesis). Conclusion We have found significant differences in skin gene expression and longitudinal change in serum markers by autoantibody specificity in dcSSc. Our findings have implications for SSc pathogenesis and support stratification by ANA subgroup in clinical studies. Disclosure K.E. Clark: None. C. Campochiaro: None. E. Csomor: Corporate appointments; employee of GSK. A. Taylor: Corporate appointments; employee of GSK. K. Nevin: Corporate appointments; employee of GSK. N. Galwey: Corporate appointments; employee of GSK. M.A. Morse: Corporate appointments; employee of GSK. V.H. Ong: None. E. Derrett-Smith: None. N. Wisniacki: Corporate appointments; employee of GSK. S. Flint: Corporate appointments; employee of GSK. C.P. Denton: Consultancies; Actelion, GlaxoSmithKline, Bayer, Sanofi, lnventiva, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CSL Behring, UCB, Leadiant Biosciences, Corbus, Servier, Arxx Therapeutics.

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Replication-dependent irreversible topoisomerase 1 poisoning is responsible for FdUMP[10] anti-leukemic activity

Experimental Hematology ◽

10.1016/j.exphem.2012.10.007 ◽

2013 ◽

Vol 41 (2) ◽

pp. 180-188.e4 ◽

Cited By ~ 5

Author(s):

Jamie Jennings-Gee ◽

Timothy S. Pardee ◽

William H. Gmeiner

Keyword(s):

Topoisomerase 1

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Cuminaldehyde from Cinnamomum verum Induces Cell Death through Targeting Topoisomerase 1 and 2 in Human Colorectal Adenocarcinoma COLO 205 Cells

Nutrients ◽

10.3390/nu8060318 ◽

2016 ◽

Vol 8 (6) ◽

pp. 318 ◽

Cited By ~ 10

Author(s):

Kuen-daw Tsai ◽

Yi-Heng Liu ◽

Ta-Wei Chen ◽

Shu-Mei Yang ◽

Ho-Yiu Wong ◽

...

Keyword(s):

Cell Death ◽

Colorectal Adenocarcinoma ◽

Topoisomerase 1

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A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

Sensors ◽

10.3390/s21144832 ◽

2021 ◽

Vol 21 (14) ◽

pp. 4832

Author(s):

Ann-Katrine Jakobsen ◽

Josephine Geertsen Keller ◽

María Gonzalez ◽

Endika Martin-Encinas ◽

Francisco Palacios ◽

...

Keyword(s):

Dna Damage ◽

In Vitro Selection ◽

Main Function ◽

Screening System ◽

Drug Candidates ◽

Topoisomerase 1 ◽

High Throughput Drug Screening ◽

Dual Sensor ◽

Selection Of

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.

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The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

International Journal of Molecular Sciences ◽

10.3390/ijms21197162 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7162

Author(s):

Elizaveta D. Gladkova ◽

Ivan V. Nechepurenko ◽

Roman A. Bredikhin ◽

Arina A. Chepanova ◽

Alexandra L. Zakharenko ◽

...

Keyword(s):

Dna Repair ◽

Bromine Atom ◽

Sulfonate Group ◽

Repair Enzyme ◽

Topoisomerase 1 ◽

Relationship Analysis ◽

Low Toxicity ◽

Berberine Derivatives ◽

Further Development ◽

Micromolar Range

A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.

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