Genetic Processes in Eukaryotic Cells-A Cooperative Function Between Chromosomes and Extrachromosomal Circular DNA - and more?

This article describes interactions between chromosomal DNA and the ECC-DNAs. The findings indicate that particular genetic activities at the level of ECC-DNAs in the target cells with relevant potential for tumor development is in progress besides the chromosomes.

Chromosomes contain DNA with the genetic code for the blueprint of the respective organism. The Human Genome Projects (HGP) have already deciphered large parts of the DNA sequences of the human chromosomes. The “protein-coding genes represent less than 2% of the total genome sequence” [1], but careful considerations are necessary [2]. With the continuous improvements of the molecular protocols, the “number of errors when mapping …” could be reduced. [3] Apart from various sequences, e. g., belonging to Human Endogenous Retroviruses, the remaining sequences belong to the “non-coding regions” - not coding for proteins -, but contributing to regulatory factors, such as diverse forms of RNAs, transposons with various functionalities. The possible function of parts of the “non-coding regions” has gained further interest [4]. This situation may be important because of certain sequences are involved, e.g., as “enhancers”, in development of cancer [5]. Even a genetic ablation of a specified RNA locus cause “genetic disorders” that can lead to organic malformations [6].

Besides the chromosomes, Extrachromosomal Circular DNA (ECC-DNA) in eukaryotic cells is a long-known fact [7]. The ECC-DNAs have a chromosomal origin, [8] mostly (?) containing coding and non-coding sequences. They “contribute to intercellular heterogeneity in normal and tumor cells” [9].

Genetic activities of ECC-DNAs

Obviously, there is an ongoing exchange of sequences between chromosomal (CHR) DNA and ECC-DNA. These ECC-DNAs may contain coding and non-coding sequences. Studies have drawn attention because of the involvement of ECC-DNAs in the development of diseases, such as various aspects of tumors. A. These findings apply in particular to the connection of ECC-DNAs in “oncogene amplification” [10], the generation of tumors, [11-14] their pathogenesis, resp. [15] and acceleration [16]. Certain details revealed on how ECC-DNAs “remodel” genomic DNA [17].

B. Implications in degenerative processes in the CNS [18].

C. Their features might provide basics for “biomarker developments” [19] and in applications already designed for diagnostic purposes [20,21]. Cell-free tumor DNA in plasma, circulating tumor DNA (ct-DNA) diagnostics should be standardized when tacking samples from the serum/plasma of presumed or already real, “personalized ct-DNA analysis” patients [22-23]. Is discrimination required to check the picked-up sequence’s origin: CHR-DNA or ECC-DNA?

D. In Peripheral Blood Mononuclear Cells (PBMCs) of healthy individuals, ECC-DNAs were detectable; they contain sequences of the Non-Coding Region (NCR) of the Hepatitis C virus (HCV), showing individual methylation patterns (methylomes) [24].

Possible impact of ECC-DNA on the human genome project (HGP)?

The HGP is designed to reveal the sequences of the DNA of human chromosomes, as a basis for gene identification. Apart from constitutive considerations about a human reference genome, [25] a possible interacting factor on the chromosomal sequences is not mentioned: the ECC-DNAs? The point is that only the sequestration of the ECC-DNA from chromosomal DNA may warrant pure/genuine chromosomal DNA sequences, i.e., not distorted by ECC-DNAs. Have the sequencing alignments been checked at scientific standards to exclude sequences of ECC-DNAs?

Protocol to search for ECC-DNA

The “ECC splorer” protocol [26] may be a tool for this task in the aftermath. A database for ECC-DNAs is available [27].

The human reference genome

In consideration of various details, there are requests for a new human “reference genome” [28]. The facts of the interactions between CHR-DNA and ECC-DNAs, should promote basic studies to exclude sequences of ECC-DNAs.

Final comment

The ECC-DNAs in eukaryotic cells are facts; however, what is inducing their generation: individual genetic rearrangements due to endogenous triggers or upon exogenous elicitors, or both? So far, the ongoing research has drawn attention on the ECC-DNAs, mainly because of their involvement in cancer development and possible use in diagnostics. ECC-DNAs with as yet unknown other coding potential should be considered in healthy individuals. The human genome project: It requires clarification on how was explicitly excluded on scientific standards the possible influence of ECC-DNAs on the chromosomal DNA sequences; this means, among other things, possible confounding factors have to be excluded beforehand.

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