| 1. |
- Andersson, Ulrika, et al.
(author)
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MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.
- 2009
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In: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 125:4, s. 968-972
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Journal article (peer-reviewed)abstract
- The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.
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| 2. |
- Carlund, Olivia, et al.
(author)
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DNA methylation variations and epigenetic aging in telomere biology disorders
- 2023
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Journal article (peer-reviewed)abstract
- Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD.
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| 3. |
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| 4. |
- Carlund, Olivia, et al.
(author)
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Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length
- 2024
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In: Clinical Epigenetics. - : BioMed Central (BMC). - 1868-7083. ; 16:1
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Journal article (peer-reviewed)abstract
- Background: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.Results: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens.Conclusion: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.
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| 5. |
- Degerman, Sofie, 1977-, et al.
(author)
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Telomerase upregulation is a postcrisis event during senescence bypass and immortalization of two Nijmegen breakage syndrome T cell cultures
- 2010
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In: Aging Cell. - : John Wiley & Sons. - 1474-9718 .- 1474-9726. ; 9, s. 220-235
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Journal article (peer-reviewed)abstract
- Summary Our knowledge on immortalization and telomere biology is mainly based on genetically manipulated cells analyzed before and many population doublings post growth crisis. The general view is that growth crisis is telomere length (TL) dependent and that escape from crisis is coupled to increased expression of the telomerase reverse transcriptase (hTERT) gene, telomerase activity upregulation and TL stabilization. Here we have analyzed the process of spontaneous immortalization of human T cells, regarding pathways involved in senescence and telomerase regulation. Two Nijmegen breakage syndrome (NBS) T cell cultures (S3R and S4) showed gradual telomere attrition until a period of growth crisis followed by the outgrowth of immortalized cells. Whole genome expression analysis indicated differences between pre-, early post- and late postcrisis cells. Early postcrisis cells demonstrated a logarithmic growth curve, very short telomeres and, notably, no increase in hTERT or telomerase activity despite downregulation of several negative hTERT regulators (e.g. FOS, JUN D, SMAD3, RUNX2, TNF-alpha and TGFbeta-R2). Thereafter, cMYC mRNA increased in parallel with increased hTERT expression, telomerase activity and elongation of short telomeres, indicating a step-wise activation of hTERT transcription involving reduction of negative regulators followed by activation of positive regulator(s). Gene expression analysis indicated that cells escaped growth crisis by deregulated DNA damage response and senescence controlling genes, including downregulation of ATM, CDKN1B (p27), CDKN2D (p19) and ASF1A and upregulation of CDK4, TWIST1, TP73L (p63) and SYK. Telomerase upregulation was thus found to be uncoupled to escape of growth crisis but rather a later event in the immortalization process of NBS T cell cultures.
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| 6. |
- Ekblom, Kim, 1970-, et al.
(author)
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Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting
- 2010
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In: Cerebrovascular Diseases. - : S. Karger. - 1015-9770 .- 1421-9786. ; 30:6, s. 590-596
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Journal article (peer-reviewed)abstract
- Background: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase-1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke, have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting.Methods: Cases with first-ever ischemic stroke (n=231; median lag time 4.9 years), and 462 matched referents from the The Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis.Results: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%), showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analysed the strongest correlation with bilirubin was found for plasma iron.Conclusions: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke also might affect bilirubin levels.
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| 7. |
- Ekblom, Kim, 1970-, et al.
(author)
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Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting
- 2010
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In: Circulation. - Philadelphia, PA : Lippincott Williams & Wilkins. - 1942-325X .- 1942-3268. ; :3, s. 340-347
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Journal article (peer-reviewed)abstract
- Background: Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDP-glucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting.Methods and Results: 618 subjects with a first-ever myocardial infarction (median event age 60.5 years, median lag time 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases vs. referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels.Conclusion: We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation or increased elimination.
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| 8. |
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| 9. |
- Ganai, Rais Ahmad, 1983-, et al.
(author)
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Yeast DNA Polymerase epsilon Catalytic Core and Holoenzyme Have Comparable Catalytic Rates
- 2015
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In: Journal of Biological Chemistry. - USA. - 0021-9258 .- 1083-351X. ; 290:6, s. 3825-3835
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Journal article (peer-reviewed)abstract
- The holoenzyme of yeast DNApolymerase ε (Pol ε) consists of four subunits– Pol2, Dpb2, Dpb3, and Dpb4. A proteasesensitivesite results in a N-terminalproteolytic fragment of Pol2, called Pol2core,that consists of the catalytic core of Pol ε andretains both polymerase and exonucleaseactivities. Pre-steady-state kinetics showedthat the exonuclease rates on single-stranded,double-stranded, and mismatched DNA werecomparable between Pol ε and Pol2core. Singleturnover pre-steady-state kinetics alsoshowed that the kpol of Pol ε and Pol2core werecomparable when pre-loading the polymeraseonto the primer-template before adding Mg2+and dTTP. However, a global fit of the dataover six sequential nucleotide incorporationsrevealed that the overall polymerization rateand processivity was higher for Pol ε than forPol2core. The largest difference was observedwhen challenged for the formation of aternary complex and incorporation of thefirst nucleotide. Pol ε needed less than asecond to incorporate a nucleotide, butseveral seconds passed before Pol2coreincorporated detectable levels of the firstnucleotide. We conclude that the accessorysubunits and the C-terminus of Pol2 do notinfluence the catalytic rate of Pol ε butfacilitate the loading and incorporation of thefirst nucleotide by Pol ε.
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| 10. |
- Hogg, Matthew, et al.
(author)
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Structural basis for processive DNA synthesis by yeast DNA polymerase ε
- 2014
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In: Nature Structural & Molecular Biology. - : Nature Publishing Group. - 1545-9993 .- 1545-9985. ; 21:1, s. 49-56
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Journal article (peer-reviewed)abstract
- DNA polymerase ε (Pol ε) is a high-fidelity polymerase that has been shown to participate in leading-strand synthesis during DNA replication in eukaryotic cells. We present here a ternary structure of the catalytic core of Pol ε (142 kDa) from Saccharomyces cerevisiae in complex with DNA and an incoming nucleotide. This structure provides information about the selection of the correct nucleotide and the positions of amino acids that might be critical for proofreading activity. Pol ε has the highest fidelity among B-family polymerases despite the absence of an extended b-hairpin loop that is required for high-fidelity replication by other B-family polymerases. Moreover, the catalytic core has a new domain that allows Pol ε to encircle the nascent doublestranded DNA. Altogether, the structure provides an explanation for the high processivity and high fidelity of leading-strand DNA synthesis in eukaryotes
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