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Review
. 2021 Jan 26;12(2):163.
doi: 10.3390/genes12020163.

A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing

Bhabesh Kumar Tripathy  1 , Kavita Pal  2 , Snehal Shabrish  2 , Indraneel Mittra  2
Affiliations
Review

A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing

Bhabesh Kumar Tripathy et al. Genes (Basel). .

Abstract

It is estimated that 10-50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day. Repeated genomic integration of cfCh may have catastrophic consequences for the cell, such as DSBs, their faulty repair by nonhomologous end joining (NHEJ) followed by apoptosis with release of more cfCh which would integrate into genomes of surrounding cells. This can creates a vicious cycle of cfCh integration, DSBs, NHEJ, and more apoptosis, thereby providing a potential explanation as to why so many billions of cells die in the body on a daily basis. We also recount the recent observation that cfCh integration and the resulting DSBs activate inflammatory cytokines. This leads us to propose that concurrent DSBs and induction of inflammation occurring throughout life may be the underlying cause of ageing, degenerative disorders, and cancer. Finally, we discuss the prospect that agents that can inactivate/degrade cfCh may hold the key to making healthy ageing a realizable goal.

Keywords: DNA damage; NHEJ; apoptosis; cell-free chromatin; free-radicals; inflammation; mosaicism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the unique mechanism by which cell-free chromatin (cfCh) particles integrate into the genome to inflict double-strand breaks (DSBs) and to activate an inflammatory response. NHEJ: nonhomologous end-joining; NHR: nonhomologous recombination. It is to be noted that in this model damage repair response (DDR) precedes DNA damage.
See this image and copyright information in PMC

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References

    1. Partridge L., Deelen J., Slagboom P.E. Facing up to the global challenges of ageing. Nature. 2018;561:45–56. doi: 10.1038/s41586-018-0457-8. - DOI - PubMed
    1. Campisi J., Kapahi P., Lithgow G.J., Melov S., Newman J.C., Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571:183–192. doi: 10.1038/s41586-019-1365-2. - DOI - PMC - PubMed
    1. Petr M.A., Tulika T., Carmona-Marin L.M., Scheibye-Knudsen M. Protecting the Aging Genome. Trends Cell Biol. 2020;30:117–132. doi: 10.1016/j.tcb.2019.12.001. - DOI - PubMed
    1. Vijg J., Dong X. Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging. Cell. 2020;182:12–23. doi: 10.1016/j.cell.2020.06.024. - DOI - PMC - PubMed
    1. White R.R., Vijg J. Do DNA Double-Strand Breaks Drive Aging? Mol. Cell. 2016;63:729–738. doi: 10.1016/j.molcel.2016.08.004. - DOI - PMC - PubMed

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