Autonomous clocks that regulate organelle biogenesis, cytoskeletal organization, and intracellular dynamics

Abstract

How do cells perceive time? Do cells use temporal information to regulate the production/degradation of their enzymes, membranes, and organelles? Does controlling biological time influence cytoskeletal organization and cellular architecture in ways that confer evolutionary and physiological advantages? Potential answers to these fundamental questions of cell biology have historically revolved around the discussion of ‘master’ temporal programs, such as the principal cyclin-dependent kinase/cyclin cell division oscillator and the circadian clock. In this review, we provide an overview of the recent evidence supporting an emerging concept of ‘autonomous clocks,’ which under normal conditions can be entrained by the cell cycle and/or the circadian clock to run at their pace, but can also run independently to serve their functions if/when these major temporal programs are halted/abrupted. We begin the discussion by introducing recent developments in the study of such clocks and their roles at different scales and complexities. We then use current advances to elucidate the logic and molecular architecture of temporal networks that comprise autonomous clocks, providing important clues as to how these clocks may have evolved to run independently and, sometimes at the cost of redundancy, have strongly coupled to run under the full command of the cell cycle and/or the circadian clock. Next, we review a list of important recent findings that have shed new light onto potential hallmarks of autonomous clocks, suggestive of prospective theoretical and experimental approaches to further accelerate their discovery. Finally, we discuss their roles in health and disease, as well as possible therapeutic opportunities that targeting the autonomous clocks may offer.

Time-keeping and decision-making in living cells: Part I

“…Furthermore, chromosome endoreduplication [ 76 ] and basal body (centriole) amplification [ 77 ] are characteristics of certain terminally differentiated (non-dividing) cells. These observations support the ‘clock-shop' hypothesis [ 71 , 72 , 78 ], although there are opposing opinions [ 73 , 79 , 80 ]. In the future, we may expect continued debate on the possible roles of ‘autonomous clocks' in cell cycle progression.…”

Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

“…While considerable progress has been made toward understanding the biophysical properties and the biological functions of biomolecular condensates and LLPS ( 38 ), it remains elusive whether LLPS dynamics are under the control of “autonomous clocks” ( 39 ). Our study hereby demonstrates the existence of an evolutionarily conserved XBP1s-SON axis that integrates the 12-hour oscillator with nuclear speckle LLPS to spatiotemporally program proteostasis ( Fig.…”

Cytoplasmic divisions without nuclei

“…This is in contrast to the autonomous cycles of centriole duplications, which occur at a natural period of ~17min, where nuclear cycles appear to help speed up centriole biogenesis in wild-type conditions (11). Together, these findings provide a striking new evidence for the emerging concept of "autonomous clocks" in which the Cdk-cyclin oscillator is postulated to couple otherwise autonomous biological cycles to run at the pace of nuclear cycles (7,11,40,41).…”

“…Prevailing models of mitotic progression have long promoted the idea that the rising levels of Cyclin-dependent kinase 1 (Cdk1) activity ( 3, 4 ) and/or affinity for substrates ( 5, 6 ) triggers cell cycle events. Recent work, however, has clearly demonstrated that some events can happen independently of Cdk1 activity ( 7, 8 ). For instance, centrioles can duplicate autonomously when the cell cycle is halted, both by perturbations in dividing cells ( 9–11 ) and naturally in non-dividing cells ( 12 ).…”

“…It remains unintuitive why the autonomy of cytoplasmic divisions should be preserved, even in apparently healthy embryos. Unless it confers a physiological advantage, such autonomy would have been rendered redundant in the face of robust cell cycle enzymes through evolution ( 7 ).…”