Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes

Journal of biosciences

Naveen Kumar Nair²  Rohan Chaubal³  Deepika Gupta²  Fatema Khambatti²  Pradyumna Kumar Mishra²  Gorantla Venkata Raghuram²  Naveen Kumar Khare²  Ashwini Gaikwad²  Aishwarya Iyer²  Preeti Prasannan²  Pawan Upadhyay³  Ankita Singh³  Akshita Singh²  Indraneel Mittra1²  Amit Dutt¹ 

[1] Integrated Cancer Genomics Laboratory; Advanced Centre for Treatment, Research and Education in Cancer,Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India$$;Translational Research Laboratory, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India$$;liation>Integrated Cancer Genomics Laboratory; Advanced Centre for Treatment, Research and Education in Cancer,Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India$$

关键词: Ageing;    apoptosis;    cancer;    circulating chromatin;    circulating DNA;    circulating nucleic acids;    circulating nucleosomes;    DNA damage;    DNA damage response;    DNA double-strand breaks;    DNA repair;   

DOI  :  

来源: Indian Academy of Sciences

【 摘 要 】

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 DNA-damage-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 that circulating DNAfs and Cfs are physiological, continuously arising, endogenous DNA damaging agents with implications to ageing and a multitude of human pathologies including initiation of cancer.

【 授权许可】

Unknown