title: The same, only different - DNA damage checkpoints and their reversal throughout the cell cycle.
abstract: Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damage-induced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.
authors.affiliation: The Netherlands Cancer Institute, Division of Cell Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Indra A
authors.initials: IA
authors.lastname: Shaltiel
authors.affiliation: The Netherlands Cancer Institute, Division of Cell Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lenno
authors.initials: L
authors.lastname: Krenning
authors.affiliation: The Netherlands Cancer Institute, Division of Cell Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Wytse
authors.initials: W
authors.lastname: Bruinsma
authors.affiliation: The Netherlands Cancer Institute, Division of Cell Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands r.medema@nki.nl.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D004247:DNA / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004247:DNA
keywords: Adaptation; Competence; DNA damage checkpoints; Plk1; Recovery; Wip1