Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes.
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Date
2015-03
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Abstract
Whether nucleic acids that circulate in blood have any patho-physiological functions in the host have not been explored. We
report here that far from being inert molecules, circulating nucleic acids have significant biological activities of their own that
are deleterious to healthy cells of the body. Fragmented DNA and chromatin (DNAfs and Cfs) isolated from blood of cancer
patients and healthy volunteers are readily taken up by a variety of cells in culture to be localized in their nuclei within a few
minutes. The intra-nuclear DNAfs and Cfs associate themselves with host cell chromosomes to evoke a cellular DNAdamage-
repair-response (DDR) followed by their incorporation into the host cell genomes. Whole genome sequencing
detected the presence of tens of thousands of human sequence reads in the recipient mouse cells. Genomic incorporation of
DNAfs and Cfs leads to dsDNA breaks and activation of apoptotic pathways in the treated cells. When injected intravenously
into Balb/C mice, DNAfs and Cfs undergo genomic integration into cells of their vital organs resulting in activation of DDR
and apoptotic proteins in the recipient cells. Cfs have significantly greater activity than DNAfs with respect to all parameters
examined, while both DNAfs and Cfs isolated from cancer patients are more active than those from normal volunteers. All
the above pathological actions of DNAfs and Cfs described above can be abrogated by concurrent treatment with DNase I
and/or anti-histone antibody complexed nanoparticles both in vitro and in vivo. Taken together, our results suggest that
circulating DNAfs and Cfs are physiological, continuously arising, endogenous DNA damaging agents with implications for
ageing and a multitude of human pathologies including initiation of cancer.
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Keywords
Ageing, apoptosis, cancer, circulating chromatin, circulating DNA, circulating nucleic acids, circulating nucleosomes, DNA damage, DNA damage response, DNA double-strand breaks, DNA repair
Citation
Mittra Indraneel, Khare Naveen Kumar, Raghuram Gorantla Venkata, Chaubal Rohan, Khambatti Fatema, Gupta Deepika, Gaikwad Ashwini, Prasannan Preeti, Singh Akshita, Iyer Aishwarya, Singh Ankita, Upadhyay Pawan, Nair Naveen Kumar, Mishra Pradyumna Kumar, Dutt Amit. Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes. Journal of Biosciences. 2015 Mar; 40 (1): 91-111.