Persistent repair intermediates induce senescence.
F M FeringaJ A RaaijmakersMichael A HaddersC VaartingLibor MacůrekL HeitinkL KrenningR H MedemaPublished in: Nature communications (2018)
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.
Keyphrases
- cell cycle
- cell cycle arrest
- dna damage
- dna repair
- cell death
- pi k akt
- cell proliferation
- oxidative stress
- induced apoptosis
- dna damage response
- endothelial cells
- circulating tumor
- signaling pathway
- endoplasmic reticulum stress
- lymph node
- single molecule
- nucleic acid
- electronic health record
- single cell
- machine learning
- deep learning
- bone marrow
- binding protein