Abstract
Cancer and aging, two distinct processes of cell development, are two major problems threatening our human health and life in current days. Epigenetic studies, especially DNA methylation, have been intensively investigated on them over the years, though a lot of unanswered issues remain. In the human genome, rDNA is a highly conserved tandem repeat family playing critical roles in protein synthesis, genome stability and integrity, etc. More importantly, rDNA is the significant target of DNA methylation, and a potential association between rDNA methylation and cancer and aging has emerged recently. However, whether there is a general trend that rDNA methylation is associated with cancer and aging remains an open issue. In this study, the involvement of rDNA methylation in a series of records of cancer and aging was investigated and summarized, upon which perspectives about rDNA methylation in cancer and aging were proposed. The results showed that rDNA methylation in most cancer cases displayed a consistent pattern with hypermethylation in the coding region but with hypomethylation in the promoter region, which likely facilitates the proliferation and metastasis of cancerous cells. Distinctively, both the coding and promoter regions of rDNA become increasingly methylated during the process of aging, indicating the decline of rDNA activity. The finding of rDNA methylation also implies its potential application as an epigenetic biomarker in the diagnosis of cancer and aging. This work will shed light on our understanding of the pathogenesis, diagnosis, and treatment of cancer and aging from the perspective of rDNA methylation.
Highlights
The highly conserved 45S ribosomal DNA (45S rDNA, hereafter referred to as rDNA for simplicity) is of importance for life since it plays critical roles in ribosome synthesis and global gene transcription and expression and in the aspects of diseases, aging, genome stability, and evolution in the genomes of the vast majority of organisms [1,2,3,4,5]
Each human rDNA copy or unit (Figure 1) contains a 13 kb transcribed region that is transcribed into 45S precursor (45S-pre) ribosomal RNA (rRNA) and a 30 kb intergenic spacer (IGS) that is exclusive of transcription but contains substantial elements such as sequences of the promoter and terminator and subrepeats. rDNA sites on the chromosomes are claimed to be fragile sites for their highly repetitive structure and unstable feature, which could give rise to potential chromosome breaks, genetic diversity, and cellular senescence [6,7,8,9]
We reviewed and summarized the involvement of 5mC of rDNA in a series of research on cancer and aging. rDNA sequences in general maintain their normal status of methylation (Figure 2(b)) but in most cases display a consistent methylation pattern in cancers, that is, hypermethylation in the coding region but hypomethylation in the promoter region (Figure 2(a)), being in line with the gene body methylation paradox [64]
Summary
The highly conserved 45S ribosomal DNA (45S rDNA, hereafter referred to as rDNA for simplicity) is of importance for life since it plays critical roles in ribosome synthesis and global gene transcription and expression and in the aspects of diseases, aging, genome stability, and evolution in the genomes of the vast majority of organisms [1,2,3,4,5]. Zhou et al [31] investigated the methylation status of the rDNA promoter region during the development of cervical cancer (cervical intraepithelial neoplasia (CIN)) in 10 patients. Studies in human hepatocellular carcinomas revealed significant hypomethylation in the rDNA promoter of the cancerous tissues compared with that of the normal control samples, accompanied by increased rRNA synthesis [2].
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