LINE-1 methylation status of endogenous DNA double-strand breaks

Pornthanakasem, Wichai; Kongruttanachok, Narisorn; Phuangphairoj, Chutipa; Suyarnsestakorn, Chotika; Sanghangthum, Taweap; Oonsiri, Sornjarod; Ponyeam, Wanpen; Thanasupawat, Thatchawan; Matangkasombut, Oranart; Mutirangura, Apiwat

doi:10.1093/nar/gkn261

Cited by 48 publications

(119 citation statements)

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“…Heterochromatin may act as a shield to prevent DNA exposure to DNA damaging agents and radiation and also reduce DNA activity such as transcription and DNA replication [41]. 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].…”

Section: Discussionmentioning

confidence: 75%

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: 75%

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

et al. 2018

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“…The expression of LINE-1 in normal tissues and cells is very low (Roman-Gomez et al, 2005;Goodier et al, 2007), but increases significantly and shows greater activity in most immortalized and malignant cells (Pornthanakasem et al, 2008). Activated LINE-1 can also promote a variety of tumor cell transformations (Gasior et al, 2006;Xing et al, 2009), and is closely related with the development of a variety of tumors, such as breast cancer, lung cancer, and others (Estécio et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The LINE-1 gene consists of two open reading frame (ORFs), ORF-1 and ORF-2, which encode the proteins LINE-1 ORF-1p and LINE-1 ORF-2p, respectively (Roman-Gomez et al, 2005). Previous studies of LINE-1 ORF-2p has mainly concentrated on the obvious retrotransposon activation of LINE-1 (Gasior et al, 2006;Goodier et al, 2007;Pornthanakasem et al, 2008). However, the specific roles and detailed mechanisms of LINE-1 ORF-1p remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…However, the specific roles and detailed mechanisms of LINE-1 ORF-1p remain largely unknown. LINE-1 ORF-1p can bind with its own DNA and RNA, playing roles as a LINE-1 ORF-2p co-regulator (Gasior et al, 2006;Goodier et al, 2007;Pornthanakasem et al, 2008;Xing et al, 2009). LINE-1 ORF-1p is widely expressed in tumor tissues, and likely promotes cell carcinogenesis through affecting the structure of chromatin (Roman-Gomez et al, 2005;Martin, 2006;Estécio et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Long interspersed nucleotide acid element-1 ORF-1 protein promotes proliferation and invasion of human colorectal cancer LoVo cells through enhancing ETS-1 activity

Li¹,

Zhu²,

Feng³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The human proto-oncogene long interspersed nucleotide acid element-1 (LINE-1) open reading frame-1 protein (ORF-1p) is involved in the progress of several cancers. The transcription factor ETS-1 can mediate the transcription of some downstream genes that play specific roles in the regulation of cancerous cell invasion and metastasis. In this study, the effects of LINE-1 ORF-1p on ETS-1 activity and on the proliferation and invasion of human colorectal cancer LoVo cells were investigated. Results showed that the overexpression of LINE-1 ORF1p enhanced the transcription of ETS-1 downstream genes and increased their protein levels, and downregulation of the LINE-1 ORF-1p level by small interfering RNA (siRNA) reduced the transcriptional activation of ETS-1. In addition, overexpression of LINE-1 ORF-1p promoted LoVo cell proliferation and anchor-independent growth, and a knockdown of the LINE-1 protein level by siRNA reduced the proliferation and anchorindependent growth ability of LoVo cells. In vivo data revealed that LINE-1 ORF-1p overexpression increased LoVo tumor growth in nude mice, whereas the siRNA knockdown of endogenous LINE-1 ORF-1p expression decreased LoVo cell growth in nude mice. Therefore, LINE-1 ORF-1p could promote LoVo cell proliferation and invasion both in vitro and in vivo, indicating that it might be a useful molecular target for the treatment of human colorectal cancer.

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“…Changes in the DNA methylation status also contribute to a higher risk of carcinogenesis, including hypermethylation of tumor suppressor genes (Das and Singal, 2004) and genome-wide hypomethylation (Kitkumthorn and Mutirangura, 2011). Genome-wide hypomethylation can promote carcinogenesis, primarily by lowering the rate of replication-independent DNA double-strand breaks and consequently promoting genomic instability (Pornthanakasem et al, 2008;Kongruttanachok et al, 2010;Thongsroy et al, 2013 Alu elements are members of the short-interspersed nuclear element (SINE) family. These elements are distributed throughout the genome, with over 1 million copies per genome, and they account for approximately 11% of the human genome.…”

Section: Introductionmentioning

confidence: 99%

Alu Methylation in Serum from Patients with Nasopharyngeal Carcinoma

Tiwawech¹,

Srisuttee²,

Rattanatanyong³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. Alu elements are among the most prevalent repetitive sequences and constitute 11% of the human genome. Although Alu methylation has been evaluated in many types of cancer, few studies have examined the levels of this modification in serum from NPC patients. Objective: To compare the Alu methylation levels and patterns between serum from NPC patients and normal controls. Materials and Methods: Sera from 50 NPC patients and 140 controls were examined. Quantitative combined bisulfite restriction analysis-Alu (qCOBRA-Alu) was applied to measure Alu methylation levels and characterize Alu methylation patterns. Amplified products were classified into four patterns according to the methylation status of 2 CpG sites: hypermethylated (methylation at both loci), partially methylated (methylation of either of the two loci), and hypomethylated (unmethylated at both loci). Results: A comparison of normal control sera with NPC sera revealed that the latter presented a significantly lower methylation level (p=0.0002) and a significantly higher percentage of hypomethylated loci (p=0.0002). The sensitivity of the higher percentage of Alu hypomethyted loci for distinguishing NPC patients from normal controls was 96%. Conclusions: Alu elements in the circulating DNA of NPC patients are hypomethylated. Moreover, Alu hypomethylated loci may represent a potential biomarker for NPC screening.

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LINE-1 methylation status of endogenous DNA double-strand breaks

Cited by 48 publications

References 44 publications

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

Alu siRNA to Increase Alu Element Methylation and Prevent DNA Damage

Long interspersed nucleotide acid element-1 ORF-1 protein promotes proliferation and invasion of human colorectal cancer LoVo cells through enhancing ETS-1 activity

Alu Methylation in Serum from Patients with Nasopharyngeal Carcinoma

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