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Cancer Prevention & Current Research

Mini Review Volume 10 Issue 1

“Dark matter of genome” in cancer

Tamara Lushnikova

Department of Pathology and Microbiology, University of Nebraska Medical Center, USA

Correspondence: Tamara Lushnikova, Department of Pathology and Microbiology, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495, USA

Received: September 20, 2017 | Published: February 14, 2019

Citation: Lushnikova T. “Dark matter of genome” in cancer. J Cancer Prev Curr Res. 2019;10(1):27-28. DOI: 10.15406/jcpcr.2019.10.00385

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Abstract

Cancer is a complex disease involved defects in hundreds of genes and multiple errors in cell intra- and extracellular networks. There are more than 100 types of tumors. Every type of cells in every tissue of the body may be changed to abnormal cell growth. What is the actual trigger for cancer? Genetic alterations in tumor suppressor genes, mutations or amplifications in oncogene genes (and MYC-containing dmin) can influence on metabolic pathways, proteome imbalances and cause the development of neoplasms.1–6 Defective DNA replication can result in genomic instability as DNA alterations, chromosomal rearrangements, aneuploidy, and gene amplifications which associated with tumors.7 Chromosomal instability (CIN) is subtype of genomic instability that cause the defects in chromosomal organization and segregation.8 How “junk” DNA may be functionally involved in tumorigenesis?

Keywords: genomic instability, “junk” DNA, “dark matter of genome”, repetitive sequences, non-coding transcripts, transposable elements

Introduction

Genomic instability is a hallmark of a cancer due to defects in repair genes

Since late 60-th it is known that the most of genomic DNA of eukaryotic organisms consists from non-coding proteins sequences, various repetitive sequences. Later among repetitive and non-coding “junk” DNA or “dark matter of genome” retrotransposons were found, short interspersed nuclear elements SINEs or long short interspersed nuclear elements and LINE,9 gene controlling elements.  For many years the scientists were focused on DNA sequences of genes, a small portion of genome coding proteins.  Carcinogen aflatoxin B1 covalently binding to DNA showed that DNA repair was deficient in repetitive satellite DNA compare in bulk DNA despite of the initial level of modification was the same in both DNAs.10 Microsatellite mutations associate with cancers and aging.11 Tumor suppressor p53 is multifunctional transcription factor, "the guardian of the  genome", the most frequently mutated gene in tumors contributes in silencing of repeats and noncoding RNAs. The p53 protein mediates expression ~1000 genes and transcription of the repeats and ncRNAs.12 Many p53 binding sites reside in transposable repeats.13 Mouse oncogene Mdm2 is a negative  regulator of p53 and DNA repair genes, is overexpressed in tumors and  contributes to chromosomal breaks (double-strand breaks, DSBs) and CIN at higher rate in transgenic Mdm2 mice with aging than in wild-type mice.14 The DNA sequences associated with chromosomal breaks and rearrangements are not well understood. The DNA breaks are formed as mistakes in DNA replication, transposition of mobile elements or by environmental agents. DSBs are random but some of them occurred on fragile sites what are near telomere or centromere. The precise genome-mapping of DSBs in human chromosomes revealed non-random fragmentation and DSB hot spots.15

Conclusion

Healing of DSBs by a retrotransposon was discussed in addition to  two known mechanisms of DNA repair, homology directed repair (HDR) and non-homologous end-joining (NHEJ) despite that mobile elements are viewed as genetic parasites.16 Transcript-templated repair of DNA double-strand breaks is possible  when RNA transcripts are used as templates for HDR.17 The advances in sequencing technology and the Encyclopedia of DNA Elements (ENCODE) highlighted the “dark matter of genome” non-coding transcripts (ncRNAs: miRNAs, piRNAs, siRNAs ) in funding of the new functional regulatory regions.18 Bioinformatics allows to detect transposable elements transcripts from RNA-seq data for characterization of novel insertions from DNA-seq data from the Cancer Genome Atlas (TCGA) what matched normal  and primary tumor samples. Several families of transposable elements in human genome are active in tumorigenesis causing numerous insertion mutations.19

Acknowledgments

None.

Conflict of interest

None.

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