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

Bhabesh Kumar Tripathy,Snehal Shabrish,Kavita Pal,Indraneel Mittra

doi:10.3390/genes12020163

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.

Highlights

What causes ageing and age-related diseases? These questions still do not have their final answers [1,2]
What causes double-strand breaks (DSBs)? In this review, we propose that the currently accepted mechanisms may not fully explain the high frequency of DSBs that are seen daily in healthy cells and propose a new mechanism implicating cell-free chromatin particles that are released from billions of cells that die in the body every day
We have summarized the currently accepted mechanisms that underlie DSBs and conclude that none of them can fully explain the high frequency of DSBs that occur in nucleated human cells per cell cycle on a daily basis (10–50/cell) under normal physiological conditions

Summary

Introduction

What causes ageing and age-related diseases? These questions still do not have their final answers [1,2]. Hydroxyl (OH·) radicals, one of the most damaging free radicals, react with nucleotide bases and deoxyribose sugars and introduce chemical modifications in them, including the formation of abasic sites and generation of single-strand breaks (SSBs) in DNA [31]. DNA polymerase may stall when it encounters these lesions, thereby disrupting the replication fork, leading to formation of DSBs [38,39,40] This hypothesis may not be applicable to neuronal cells that do not divide, and especially since DSBs in brain increase progressively with age and are linked with neurodegenerative disorders, like Alzheimer’s disease [41]. We provide below one such new mechanism which involves DSBs inflicted by genomic integration of cell-free chromatin (cfCh) particles released from dying cells

Cell-Free Chromatin: A Continuously Arising Trigger for DSBs

Is it cfCh or cfDNA that Cause DSBs?

Conclusions

Future Prospects