Unchecked nick ligation can promote localized genome re-replication

Erik Johansson,John F.X Diffley

doi:10.1016/j.cub.2021.03.043

Erik Johansson, John F.X Diffley

Open Access

https://doi.org/10.1016/j.cub.2021.03.043

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Abstract

SummarySingle-stranded DNA breaks, or nicks, are amongst the most common forms of DNA damage in cells. They can be repaired by ligation; however, if a nick occurs just ahead of an approaching replisome, the outcome is a collapsed replication fork comprising a single-ended double-strand break and a ‘hybrid nick’ with parental DNA on one side and nascent DNA on the other (Figure 1A). We realized that in eukaryotic cells, where replication initiates from multiple replication origins, a fork from an adjacent origin can promote localized re-replication if the hybrid nick is ligated. We have modelled this situation with purified proteins in vitro and have found that there is, indeed, an additional hazard that eukaryotic replisomes face. We discuss how this problem might be mitigated.

Highlights

Single-stranded DNA breaks, or nicks, are amongst the most common forms of DNA damage in cells
We realized that in eukaryotic cells, where replication initiates from multiple replication origins, a fork from an adjacent origin can promote localized re-replication if the hybrid nick is ligated
If the hybrid nick is ligated before fork B reaches it (iii), fork B can continue replicating beyond the position of the nick, resulting in re-replication

Summary

Introduction

Single-stranded DNA breaks, or nicks, are amongst the most common forms of DNA damage in cells. We realized that in eukaryotic cells, where replication initiates from multiple replication origins, a fork from an adjacent origin can promote localized re-replication if the hybrid nick is ligated.

Results

Conclusion