The Hammer and the Dance of Cell Cycle Control

Abstract

Cell cycle checkpoints secure ordered progression from one cell cycle phase to the next. They are important to signal cell stress and DNA lesions and to stop cell cycle progression when severe problems occur. Recent work suggests, however, that the cell cycle control machinery responds in more subtle and sophisticated ways when cells are faced with naturally occurring challenges, such as replication impediments associated with endogenous replication stress. Instead of following a stop and go approach, cells use fine-tuned deceleration and brake release mechanisms under the control of ataxia telangiectasia and Rad3-related protein kinase (ATR) and checkpoint kinase 1 (CHK1) to more flexibly adapt their cell cycle program to changing conditions. We highlight emerging examples of such intrinsic cell cycle checkpoint regulation and discuss their physiological and clinical relevance. From Stop and Go Cell Cycle Decisions to a Continuum of Deceleration and Brake Release MechanismsCell cycle checkpoints (see Glossary) are control mechanisms that ensure proper and ordered progression of cells through the cell cycle [1]. Genome integrity maintenance is among the key tasks of cell cycle checkpoint control, and DNA damage checkpoints have thus evolved to trigger cell cycle arrest in response to genomic lesions and allow time for repair [2]. The cell cycle checkpoint model, in agreement with the general meaning of the term checkpoint, implies certain criteria, which have to be met by a cell to continue its progression through the cell cycle (the 'go' decision) and which, if they are not fulfilled, lead to transient or permanent cell cycle arrest (the 'stop' decision). Among the major cell cycle checkpoints are the G1/S checkpoint, the G2/M checkpoint, and the spindle checkpoint in mitosis. By analogy to 'the hammer and the dance' metaphor introduced early in 2020 by Tomas Pueyo to emphasize the importance of acting quickly and forcefully to contain the global health threat posed by SARS-CoV-2 and later ease and adapt the measures to continually manage and control COVID-19 ('Coronavirus: the hammer and the dance', published online March 19, 2020; https://medium.com/@tomaspueyo/coronavirus-the-hammerand-the-dance-be9337092b56), we can consider full checkpoint activation to halt cell cycle progression as 'the hammer', which can be an effective means to minimize further damage in the face of severe threats to genome integrity. However, rather than relying exclusively on binary stop and go decisions, a picture is starting to emerge in which the cell cycle control machinery uses fine-tuned brakes and brake release mechanisms [3], thereby temporarily decelerating certain processes while continuing others, to globally balance genome surveillance with cell cycle progression ('the dance'). Thus, cell cycle arrest as an extreme measure seems reserved for severe events that threaten genome integrity and cell survival, while more moderate and adaptable measures are commonly used by cells to deal with controllable genomic lesions and repl...

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