Genomic instability in patients with type 2 diabetes mellitus on hemodialysis

Palazzo, Roberta Passos; Bagatini, Pamela Brambilla; Schefer, Patrícia Brandt; Andrade, Fabiana Michelsen de; Maluf, Sharbel Weidner

doi:10.5581/1516-8484.20120011

Cited by 22 publications

(11 citation statements)

References 22 publications

(26 reference statements)

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“…Our data suggest that i-motif formation can block replication, and this, in turn, may result in genomic instability. Genomic instability is associated with cancer development and also with chronic diseases, such as diabetes (45,46). It is possible that mutation in or dysregulation of expression of i-motif-binding proteins or the acidic pH of the cancer cell environment may promote or lead to stabilization of i-motif formation.…”

Section: Discussionmentioning

confidence: 99%

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Takahashi

Brazier

Sugimoto

2017

Proc. Natl. Acad. Sci. U.S.A.

106

110

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Noncanonical DNA structures that stall DNA replication can cause errors in genomic DNA. Here, we investigated how the noncanonical structures formed by sequences in genes associated with a number of diseases impacted DNA polymerization by the Klenow fragment of DNA polymerase. Replication of a DNA sequence forming an i-motif from a telomere, hypoxia-induced transcription factor, and an insulin-linked polymorphic region was effectively inhibited. On the other hand, replication of a mixed-type G-quadruplex (G4) from a telomere was less inhibited than that of the antiparallel type or parallel type. Interestingly, the i-motif was a better inhibitor of replication than were mixed-type G4s or hairpin structures, even though all had similar thermodynamic stabilities. These results indicate that both the stability and topology of structures formed in DNA templates impact the processivity of a DNA polymerase. This suggests that i-motif formation may trigger genomic instability by stalling the replication of DNA, causing intractable diseases.oncanonical intramolecular structures of nucleic acids, such as a triplex and a quadruplex, are stabilized under conditions that mimic the crowded cellular conditions (1), and have been detected in cells (2, 3). In vitro and in vivo, guaninequadruplex (G-quadruplex or G4) formation inhibits transcription and translation of template nucleic acids (4-8). It is possible that the noncanonical structures act as "functional codes" triggered by different molecular environments, which regulate gene expression epigenetically (6, 7). As sequences capable of forming the noncanonical structures are found in telomeres and promoter regions of known oncogenes, alterations of the noncanonical structures could play important roles in the progression of cancer and in other diseases (9).One of the remarkable features of noncanonical structures of nucleic acids is the diversity of topologies. In the case of G4s, antiparallel, mixed, and parallel type structures have been characterized ( Fig. 1 A-C). The sequences complementary to regions capable of G4 formation are composed of tandem repeats of cytosine, and these C-rich regions can form a different type of tetraplex topology, which is the i-motif (10, 11). An intramolecular i-motif is formed upon the interaction of four C-rich regions. The structure has three loops and two parallel-stranded hairpin-like units stabilized by cytosine and protonated cytosine (C:C + ) base pairs that are vertically intercalated antiparallel to one another ( Fig. 1 D and E). The i-motif structures are categorized into class I and class II based on the lengths of the loops. C-rich sequences are found in telomeres and in the promoter regions of about 40% of human genes (12, 13). As the i-motif is stabilized by hydrogen bonding in C:C + base pairs (14, 15), acidic conditions stabilize the structure. As the i-motif can mediate transcriptional regulation of B-cell lymphoma 2 (Bcl2) oncogene in cells (16), the environment inside these cells might be favorable to i-motif formation....

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Section: Discussionmentioning

confidence: 99%

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Takahashi

Brazier

Sugimoto

2017

Proc. Natl. Acad. Sci. U.S.A.

106

110

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“…DNA instability has long been noted in COPD [46] and more recently described in T2D [47] and atherosclerosis [48]. Epigenetic modifications, including changes in histone deacetylase 2 activity, have been identified in all three conditions [49][50][51].…”

Section: Theme 1: Accelerated Ageing In Multimorbiditymentioning

confidence: 99%

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

2020

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Multimorbidity is increasingly common and current healthcare strategies are not always aligned to treat this complex burden of disease. COPD, type-2 diabetes mellitus (T2D) and cardiovascular disease, especially atherosclerosis, occur more frequently together than expected, even when risk factors such as smoking, obesity, inactivity and poverty are considered. This supports the possibility of unifying mechanisms that contribute to the pathogenesis or progression of each condition.Neutrophilic inflammation is causally associated with COPD, and increasingly recognised in the pathogenesis of atherosclerosis and T2D, potentially forming an aetiological link between conditions. This link might reflect an overspill of inflammation from one affected organ into the systemic circulation, exposing all organs to an increased milieu of proinflammatory cytokines. Additionally, increasing evidence supports the involvement of other processes in chronic disease pathogenesis, such as cellular senescence or changes in cellular phenotypes.This review explores the current scientific evidence for inflammation, cellular ageing and cellular processes, such as reactive oxygen species production and phenotypic changes in the pathogenesis of COPD, T2D and atherosclerosis; highlighting common mechanisms shared across these diseases. We identify emerging therapeutic approaches that target these areas, but also where more work is still required to improve our understanding of the underlying cellular biology in a multimorbid disease setting.

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“…It is well known that patients with type 2 diabetes have elevated levels of DNA damage (Al-Aubaidy and Jelinek 2011, Palazzo et al 2012, Binici et al 2013, Tatsch et al 2015. DNA damage was shown to occur as a consequence of oxidative stress in several diseases, including diabetes (Rösen et al 2001, Kowluru andMishra 2015).…”

Section: Introductionmentioning

confidence: 99%

High consumption of sucrose induces DNA damage in male Wistar rats

Franke

Molz

Mai

et al. 2017

An. Acad. Bras. Ciênc.

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The purpose of this study was to determine the effects of the high consumption of sucrose on the levels of DNA damage in blood, hippocampus and bone marrow of rats. Male Wistar rats were treated for 4 months with sucrose (10% for 60 initial days and 34% for the following 60 days) in drinking water, and then, glycemia and glycated hemoglobin (A1C) were measured. Levels of DNA damage in blood and hippocampus were evaluated by the comet assay. The micronucleus test was used to evaluate chromosomal damages in the bone marrow. The sucrose treatment significantly increased (p<0.01) the serum glucose levels (~20%) and A1C (~60%). The level of primary DNA damage was significantly increased (p<0.05) in hippocampal cells (~60%) but not in peripheral blood leukocytes (p>0.05). Additionally, it was observed a significative increase (p<0.05) in the markers of chromosomal breaks/losses in bone marrow, as indicated by the micronucleus test. This is the first study that evaluated DNA damage induced by high sucrose concentration in the hippocampus and bone marrow of rats. Sucrose-induced DNA damage was observed in both tissues. However, the mechanism of sucrose toxicity on DNA remains unknown.

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Genomic instability in patients with type 2 diabetes mellitus on hemodialysis

Cited by 22 publications

References 22 publications

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

High consumption of sucrose induces DNA damage in male Wistar rats

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