Abstract
BackgroundWe have recently reported that cell-free DNA (cfDNA) fragments derived from dying cells that circulate in blood are biologically active molecules and can readily enter into healthy cells to activate DNA damage and apoptotic responses in the recipients. However, DNA is not conventionally known to spontaneously enter into cells or to have any intrinsic biological activity. We hypothesized that cellular entry and acquisition of biological properties are functions of the size of DNA.ResultsTo test this hypothesis, we generated small DNA fragments by sonicating high molecular weight DNA (HMW DNA) to mimic circulating cfDNA. Sonication of HMW DNA isolated from cancerous and non-cancerous human cells, bacteria and plant generated fragments 300–3000 bp in size which are similar to that reported for circulating cfDNA. We show here that while HMW DNAs were incapable of entering into cells, sonicated DNA (sDNA) from different sources could do so indiscriminately without heed to species or kingdom boundaries. Thus, sDNA from human cells and those from bacteria and plant could enter into nuclei of mouse cells and sDNA from human, bacterial and plant sources could spontaneously enter into bacteria. The intracellular sDNA associated themselves with host cell chromosomes and integrated into their genomes. Furthermore, sDNA, but not HMW DNA, from all four sources could phosphorylate H2AX and activate the pro-inflammatory transcription factor NFκB in mouse cells, indicating that sDNAs had acquired biological activities.ConclusionsOur results show that small fragments of DNA from different sources can indiscriminately enter into other cells across species and kingdom boundaries to integrate into their genomes and activate biological processes. This raises the possibility that fragmented DNA that are generated following organismal cell-death may have evolutionary implications by acting as mobile genetic elements that are involved in horizontal gene transfer.
Highlights
We have recently reported that cell-free high molecular weight DNA (DNA) fragments derived from dying cells that circulate in blood are biologically active molecules and can readily enter into healthy cells to activate DNA damage and apoptotic responses in the recipients
We have recently reported that fragmented cell-free DNA (cfDNA) that circulate in human blood are readily taken up by mammalian cells but that they can evoke biological responses in the recipients [3, 4, 6, 15]
We show that while high molecular weight DNA (HMW DNA) were incapable of entering into cells, sonicated DNA from various sources were taken up by each other indiscriminately without heed to species or kingdom boundaries
Summary
We have recently reported that cell-free DNA (cfDNA) fragments derived from dying cells that circulate in blood are biologically active molecules and can readily enter into healthy cells to activate DNA damage and apoptotic responses in the recipients. We have recently reported that fragmented cfDNA that circulate in human blood are readily taken up by mammalian cells but that they can evoke biological responses in the recipients [3, 4, 6, 15]. Damage to DNA activated an apoptotic response resulting in death of some cells [4].Taken together, the above studies support the observation that fragmented cfDNAs can be internalized by healthy cells with potentially oncogenic consequences
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