"Dark matter of genome” in cancer

Abstract

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