The Hammer and the Dance of Cell Cycle Control

Shutdown of cell cycle progression by checkpoint activation is the exception rather than norm when cells face physiological levels replication stress.In response to endogenous stress, use tunable deceleration and brake release mechanisms under control ATR CHK1 kinases for timely completion DNA duplication.Intrinsic activation, maintenance, recovery represent a continuum, which modulated phosphorylation ubiquitin-dependent proteasomal degradation.Sharp transitions, in one phase fully concluded before next begins, can be blurred due balancing act between genome integrity maintenance an urge completion.Deviations from ordered transitions promote cancer, with therapeutic opportunities kinase inhibitors. Cell checkpoints secure next. They are important signal stress lesions stop severe problems occur. Recent work suggests, however, that machinery responds more subtle sophisticated ways faced naturally occurring challenges, such as impediments associated stress. Instead following go approach, fine-tuned ataxia telangiectasia Rad3-related protein (ATR) 1 (CHK1) flexibly adapt their program changing conditions. We highlight emerging examples intrinsic regulation discuss clinical relevance. (see Glossary) ensure proper through [1.Hartwell L.H. Weinert T.A. Checkpoints: controls order events.Science. 1989; 246: 629-634Crossref PubMed Google Scholar]. Genome among key tasks control, damage have thus evolved trigger arrest genomic allow time repair [2.Zhou B.B. Elledge S.J. The response: putting perspective.Nature. 2000; 408: 433-439Crossref Scopus (2483) model, agreement general meaning term checkpoint, implies certain criteria, met continue its (the ‘go’ decision) which, if they not fulfilled, lead transient or permanent ‘stop’ decision). Among major G1/S G2/M spindle mitosis. By analogy ‘the hammer dance’ metaphor introduced early 2020 Tomas Pueyo emphasize importance acting quickly forcefully contain global health threat posed SARS-CoV-2 later ease measures continually manage COVID-19 (‘Coronavirus: dance’, published online March 19, 2020; https://medium.com/@tomaspueyo/coronavirus-the-hammer-and-the-dance-be9337092b56), we consider full halt hammer’, effective means minimize further threats integrity. However, relying exclusively on binary decisions, picture starting emerge uses brakes [3.Lemmens B. Lindqvist A. mitotic entry: model progression.J. Biol. 2019; 218: 3892-3902Crossref Scholar], thereby temporarily decelerating processes while continuing others, globally balance surveillance (‘the dance’). Thus, extreme measure seems reserved events threaten survival, moderate adaptable commonly used deal controllable intermediates flexible context-specific manner. 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