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

1
Indian Institute of Science Education and Research (IISER), Tirupati 517507, India
2
Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) and Homi Bhabha National Institute, Mumbai 410210, India
*
Author to whom correspondence should be addressed.
Academic Editor: Karen Mather
Received: 11 November 2020 / Revised: 19 January 2021 / Accepted: 19 January 2021 / Published: 26 January 2021
(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)
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. View Full-Text
Keywords: free-radicals; cell-free chromatin; apoptosis; DNA damage; NHEJ; mosaicism; inflammation free-radicals; cell-free chromatin; apoptosis; DNA damage; NHEJ; mosaicism; inflammation
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MDPI and ACS Style

Tripathy, B.K.; Pal, K.; Shabrish, S.; Mittra, I. A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing. Genes 2021, 12, 163. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020163

AMA Style

Tripathy BK, Pal K, Shabrish S, Mittra I. A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing. Genes. 2021; 12(2):163. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020163

Chicago/Turabian Style

Tripathy, Bhabesh K., Kavita Pal, Snehal Shabrish, and Indraneel Mittra. 2021. "A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing" Genes 12, no. 2: 163. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020163

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