Replication independent DNA double-strand break retention may prevent genomic instability

Kongruttanachok, Narisorn; Phuangphairoj, Chutipa; Thongnak, Araya; Ponyeam, Wanpen; Rattanatanyong, Prakasit; Pornthanakasem, Wichai; Mutirangura, Apiwat

doi:10.1186/1476-4598-9-70

Cited by 51 publications

(70 citation statements)

References 79 publications

(120 reference statements)

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“…Second, we observed accumulation of replication-independent endogenous DNA double strand breaks (RIND-EDSBs) in hypermethylate genome [42]. Our recent study indicated that RIND-EDSBs may possess an epigenetic role in reducing DNA strain similar to a small gap between two railway lines [43][44][45]. Third, DNA repair activity is different depending on chromatin structure [46,47].…”

Section: Discussionmentioning

confidence: 90%

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

et al. 2018

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Global DNA hypomethylation promoting genomic instability leads to cancer and deterioration of human health with age. Aim: To invent a biotechnology that can reprogram this process. Methods: We used Alu siRNA to direct Alu interspersed repetitive sequences methylation in human cells. We evaluated the correlation between DNA damage and Alu methylation levels. Results: We observed an inverse correlation between Alu element methylation and endogenous DNA damage in white blood cells. Cells transfected with Alu siRNA exhibited high Alu methylation levels, increased proliferation, reduced endogenous DNA damage and improved resistance to DNA damaging agents. Conclusion: Alu methylation stabilizes the genome by preventing accumulation of DNA damage. Alu siRNA could be useful for evaluating reprograming of the global hypomethylation phenotype in cancer and aging cells. DNA methylation at interspersed repetitive sequences (IRSs) plays an important role in maintaining genome stability. Cells with IRS hypomethylation exhibit increased mutation rates [1,2]. Here, we tested whether DNA damage, an alteration in the chemical structure of DNA and a precursor to mutation [3], plays a role in mediating how global hypomethylation promotes genomic instability. Our recent study found that global hypomethylation is associated with plasma 8-hydroxy-2 -deoxyguanosine (8-OHdG) in biliary atresia patients [4]. Moreover, urinary 8-OHdG, DNA strand breaks and global DNA hypomethylation are associated with low serum folate [5] and oxidative stress [6]. Therefore, we hypothesized that the human genome may use DNA methylation in IRSs to prevent DNA damage.This study developed a technology to add DNA methylation at Alu elements. The human genome contains greater than one million Alu elements [7]. Several reports demonstrated de novo methylation by siRNA in plants [8][9][10]. In human cells, small RNA was used to promote DNA methylation, shRNA for long interspersed element-1 (LINE-1) and hepatitis B virus, and siRNA for HIV-1 promoter region [11][12][13]. There are many types of IRS such as Alu elements, LINE-1, and human endogenous retrovirus [14][15][16][17]. To increase DNA methylation, we tested siRNA to unique sequences and several IRS sequences. Our preliminary trial demonstrated that only Alu siRNA could increase methylation of the target sequences. Here, we evaluated whether Alu siRNA is a useful tool to explore the role of global hypomethylation in genomic instability [18].Alu hypomethylation may play a role in causing genomic instability in cancer and aging cells. Genomic instability, the main enabling characteristic of cancer and aging processes [18,19], may mainly be promoted by IRS hypomethylation. IRS hypomethylation is commonly observed both in aging [14,20] and cancer cells [21]. IRS

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Section: Discussionmentioning

confidence: 90%

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

et al. 2018

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“…Genome-wide hypomethylation, which is characterized by reduced methylation levels of LINE-1 and Alu, is often present in many malignancies (Kitkumthorn, 2011). The epigenomic changes are associated with genomic instability and altered gene expression (Hoffmann, 2005;Kongruttanachok, 2010;Aporntewan, 2011). Both LINE-1 and Alu hypomethylation are also associated with advanced tumor stage, higher histological grade, poorer prognosis and RESEARCH ARTICLE…”

Section: Introductionmentioning

confidence: 99%

LINE-1 and Alu Methylation Patterns in Lymph Node Metastases of Head and Neck Cancers

Kitkumthorn

Keelawat²,

Rattanatanyong³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…6 Demethylation of transposable elements is hypothesized to facilitate genomic instability by leading to retrotransposition of transposable elements, hypomethylated genome-associated error-prone repair of replication-independent endogenous double-strand breaks, and dysregulation of DNA repair genes. [7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes located nearby, 12,13 creating chimeric transcripts, 14 or downregulating the expression of genes harboring transposable elements in their introns. subsequently to GC.…”

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confidence: 99%

“…[7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes located nearby, 12,13 creating chimeric transcripts, 14 or downregulating the expression of genes harboring transposable elements in their introns.…”

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ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.Focal promoter CpG island hypermethylation and generalized genomic hypomethylation signify the changes in the DNA methylation status in human cancer cells. Promoter CpG island hypermethylation is an important mechanism that inactivates tumor suppressor and tumor-related genes; meanwhile, generalized genomic hypomethylation contributes to genomic or chromosomal instability.1-3 Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent.5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively. 4CpG sites located within LINE-1 and ALU are usually methylated in normal somatic tissues, a mechanism that is believed to have evolved as a major defense mechanism to repress these transposable genetic elements.6 Demethylation of transposable elements is hypothesized to facilitate genomic instability by leading to retrotransposition of transposable elements, hypomethylated genome-associated error-prone repair of replication-independent endogenous double-strand breaks, and dysregulation of DNA repair genes. [7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes l...

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Replication independent DNA double-strand break retention may prevent genomic instability

Cited by 51 publications

References 79 publications

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

LINE-1 and Alu Methylation Patterns in Lymph Node Metastases of Head and Neck Cancers

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

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