Abstract
Double-stranded DNA breaks activate a DNA damage checkpoint in G2 phase to trigger a cell cycle arrest, which can be reversed to allow for recovery. However, damaged G2 cells can also permanently exit the cell cycle, going into senescence or apoptosis, raising the question how an individual cell decides whether to recover or withdraw from the cell cycle. Here we find that the decision to withdraw from the cell cycle in G2 is critically dependent on the progression of DNA repair. We show that delayed processing of double strand breaks through HR-mediated repair results in high levels of resected DNA and enhanced ATR-dependent signalling, allowing p21 to rise to levels at which it drives cell cycle exit. These data imply that cells have the capacity to discriminate breaks that can be repaired from breaks that are difficult to repair at a time when repair is still ongoing.
Highlights
Double-stranded DNA breaks activate a DNA damage checkpoint in G2 phase to trigger a cell cycle arrest, which can be reversed to allow for recovery
In the cells that do not recover from the arrest, the time of Cyclin B1 translocation is independent of the ionizing radiation (IR) dose, always occurring around 3–4 h after the damaging insult (Fig. 1a, black dots), implying that cells respond to defects in repair well before repair has been completed (Supplementary Fig. 1b)
The response to double-stranded breaks (DSBs) can vary among individual cells within a population, and we have previously shown that a difference in cell cycle stage at the moment of irradiation can affect cellular fate[1,16]
Summary
Double-stranded DNA breaks activate a DNA damage checkpoint in G2 phase to trigger a cell cycle arrest, which can be reversed to allow for recovery. When DNA lesions are encountered, the DNA damage response (DDR) activates a checkpoint signalling cascade that will halt cell cycle progression and activate DNA repair This arrest is important when DNA double-stranded breaks (DSBs) occur in G2 phase, since cells need to prevent cell division in the presence of broken chromosomes as this can lead to loss or gain of genetic material that could cause cell death, or drive transformation[1,2,3,4]. RPA needs to be exchanged for Rad[51] protein on the single-stranded DNA to start the homology search and complete HR repair[11,12] It is still largely unknown how checkpoint (in)activation and repair are coordinated to determine cell fate after DNA damage. These results show that cell fate decisions can be triggered by the detection of damage that will be difficult to repair, already in the first hours after damage induction, at a time when other breaks are still being repaired
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