Circadian rhythms coordinate biological timekeeping on a ~ 24-h timescale, aligning physiology and behavior with the daily solar cycle on Earth. The molecular clocks that generate circadian rhythms are found in both prokaryotes and eukaryotes, where they create oscillations in the abundance and/or activity of core clock proteins and clock-controlled genes that lead to temporal control of downstream processes from metabolism [1] to immune function [2] to cell division [3]. This FEBS Letters special issue on ‘Circadian clocks’ focuses on recent advances in our understanding of the molecular basis of circadian rhythms, their pervasive and powerful control of biology, and new frontiers in the field, including approaches to modulate biological timekeeping to improve human health. The review article by Liu and Sancar highlights our current understanding of the mammalian circadian clock and its impact on human health [4]. Based on genetic and biochemical studies, we now understand that the transcription/translation feedback loop (TTFL) that underlies mammalian circadian rhythms is initiated by the heterodimeric transcription factor, CLOCK:BMAL, and followed by two distinct steps of transcriptional repression mediated by other core clock components, such as the period (PER) and cryptochrome (CRY) proteins. The circadian clock directly impacts human health by influencing sleep patterns, metabolism, DNA repair and the cell cycle. Otobe and Yoshitane explain ‘in a nutshell’ how post-translational modification (PTM) of CLOCK and BMAL1 by phosphorylation regulates their activity, and describe open questions about the essential role that phosphorylation is known to play in regulating other clock components during the repressive phase of the molecular clock [5]. In their review, Rao and Srivastava share a structural viewpoint on molecular circadian clocks, describing how insights into protein structure from cyanobacteria to humans have informed our understanding of clock mechanisms [6]. They make a compelling argument that computational studies such as molecular simulations and structural modeling can be used to take us beyond current experimental limitations to bring new insight to clock protein function. Importantly, nearly all eukaryotic clock proteins have regions of extensive intrinsic disorder that are required for their function. By definition, these intrinsically disordered proteins (IDPs) lack tertiary structure—instead, they are highly dynamic in nature and often work in concert with structured domains to impart flexibility in clock protein regulation. The review by Usher and Pelham describes the interesting ensemble properties of IDPs and how they are frequently regulated by different PTMs to contribute to circadian timekeeping from humans to fungi [7]. In their perspective, Larrondo et al. detail the structure and function of a massive, predominantly disordered protein known as frequency (FRQ) in the fungal clock model system of Neurospora crassa [8]. The impact of sequence and charge distribution throughout the disordered regions of FRQ, and how phosphorylation might regulate its overall structure, serves as an excellent example for future studies of other clock proteins. Lessons about oscillator theory apply to all circadian clocks and provide a quantitative framework for understanding biological timekeeping. The review by del Olmo and Herzel provides an excellent primer on fundamental oscillator theory and illustrates how understanding the architecture of TTFLs informs basic clock properties such as entrainment, the mechanism by which circadian clocks are synchronized with external stimuli [9]. Priya Crosby describes current models of entrainment in the mammalian circadian clock [10]. In her review, she details commonalities and differences in how light, feeding, and temperature cues are interpreted at the molecular level to alter the phase of circadian rhythms. This is a fascinating and understudied area of the field; developing a better understanding of the molecular mechanisms of circadian entrainment will undoubtedly have positive effects on human health. In mammals, circadian rhythms control the expression of thousands of genes through the interlocked TTFLs and downstream pathways to impart temporal control on biological processes. Clock transcription factors also integrate directly with other pathways, particularly at the level of chromatin regulation. The perspective from Nei and Menet describes how CLOCK:BMAL1 and the circadian clock affect chromatin architecture and transcriptional plasticity throughout the genome [11]. Wang and Lamia provide a graphical review illustrating how the BMAL1 subunit interacts with other basic helix–loop–helix Per-ARNT-Sim (bHLH-PAS) proteins aside from CLOCK, such as the hypoxia inducible factor HIF2α [12]. This HIF-containing heterodimer places BMAL1 and the clock at an intersection with hypoxia signaling and its well-known impact on tumor growth. Kimmey et al. describe another exciting area where clock signaling affects biology and human health [13]. Their review describes how the timing of infection impacts host response and outcomes to bacteria such as Salmonella enterica and Streptococcus pneumoniae. Finally, in their perspective, Feord and van Oijen present evidence for the circadian regulation of intracellular magnesium levels throughout eukaryotes and describe mechanisms by which this could regulate cellular energy expenditure [14]. The evolution of circadian clocks throughout eukaryotes has relied on several conserved protein folds that can bind small molecule cofactors, adapting them in various systems to light-dependent or -independent roles. The review by Zoltowski et al. nicely describes the prevalence of the PAS domain and its light-sensing LOV (light-oxygen-voltage) variant in circadian rhythms, as well as how the CRY photolyase homology region (PHR) fold has been adapted to different roles in insects and mammals [15]. The propensity for cofactor binding has made CRYs and PAS domain-containing proteins interesting therapeutic targets. This represents an exciting new frontier in circadian rhythms—chemical biology—which is detailed by Farkas et al. in their review [16]. They describe genetic and cellular approaches to clock monitoring and perturbation, as well as its regulation by small molecules. As circadian rhythms have been well-documented in most eukaryotes, another exciting frontier is to begin studying clocks in prokaryotes. Aside from the well-studied example in cyanobacteria such as Synechococcus elongatus, the perspective by Kay and Jabbur describes the relatively nascent field of microbial chronobiology and the impact that interactions with hosts and other organisms could have on these rhythms [17]. Altogether, the pieces in this special issue aim to highlight a new focus on more molecular aspects of circadian biology, from the single-molecule footprinting studies of native transcription factors in vivo described by Nie and Menet [11] to the new mechanistic understanding of clock proteins highlighted by Liu and Sancar [4], Wang and Lamia [12], and Zoltowski et al. in their pieces [15]. It is truly an exciting time to study circadian rhythms and their intricate temporal control of biology across species from humans to microbes. Advances in experimental and computational tools are providing new insights into clock protein structure and function, and a new toolkit of small molecules and genetic engineering tools are enabling discovery of new aspects of clock-controlled biology. Carrie L. Partch is a Professor in the Department of Chemistry and Biochemistry at the University of California Santa Cruz and an Investigator with the Howard Hughes Medical Institute. Her research group has focused on the molecular basis of circadian clocks in cyanobacteria and mammals. She has a longstanding interest in understanding how protein interactions, structure, and dynamics regulate clock protein interactions and establish biological timekeeping.
Carrie L. Partch (2026) studied this question.