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Genomic integration of circulating nucleic acids and DNA damage.


Whether nucleic acids that circulate in blood (CNAs) have any patho-physiological functions in the host have not been explored. Our lab has demonstrated for the first time that CNAs in the form of fragmented DNA and chromatin (DNAfs and Cfs) can freely enter into healthy cells, associate with their chromosomes and integrate into host cell genomes. The latter leads to activation of DDR and up-regulation of apoptotic pathways. When injected intravenously into mice, DNAfs and Cfs integrate into cells of vital organs and bring about dsDNA breaks and apoptosis in a proportion of cells.

These findings lead to the conclusion 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. All the 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 suggesting therapeutic possibilities. Genomic integration of Cfs involves DNA double strand break repair. Mice were injected i.v. with Cfs (100 ng DNA) and sacrificed 24 hr later. Sections of brain were processed for immuno-FISH using human-specific genomic probe (green) and antibodies against g-H2AX (red). Co-localization of green and red signals are clearly visible.

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