Cell cycle

Constructing a minimal protein machinery for self-division of membrane compartments is a major goal of bottom-up synthetic biology. Here, authors achieved the assembly, placement and onset of contraction of a minimal division ring in lipid vesicles.

The core cell cycle is largely driven by increasing total CDK activity together with minor differences in the substrate specificity of the CDKs initiating DNA replication and mitosis.

The natural product fucoxanthinol causes G1 arrest through decreasing the levels of ribosomal protein uS7, which directly binds and stabilises cyclin-dependent kinase 6.

In addition to CDC7, the cell cycle kinase CDK1 has a pivotal role in the G1/S transition of cells, a finding that revises our current understanding of cell cycle progression.

Das et al. show that chromatin incorporation of histone H3 variant CENP-A at centromeres in early mouse embryos depends on the maternally provided Cenpa mRNA pool and on repetitive centromere satellite DNA, rather than pre-existing CENP-A nucleosomes.

Totipotent cells in mouse embryos and 2-cell-like cells have slow DNA replication fork speed. Perturbations that slow replication fork speed promote 2-cell-like cell emergence and improve somatic cell nuclear transfer reprogramming and formation of induced pluripotent stem cell colonies.

Zhao et al. report a role for glutamine synthetase in regulating cell proliferation that does not require the catalytic activity of the enzyme.

Pomp et al. show that specification of inner cell mass versus trophectoderm depends on a monoastral spindle that drives asymmetric cell division patterns, arguing against a stochastic inner–outer lineage segregation in the mouse embryo.

Entry into S phase of the cell cycle is regulated positively by mitogens and negatively by DNA damage; however, how balance of these signals is achieved is not well known. Here the authors show that the NUCKS1-SKP2- p21/p27 axis integrates this information, where the NUCKS1 transcription factor affects levels of p21/p27 to readout the mitogen:DNA damage balance and regulate S phase entry decision.

Structures of separase in complex with either securin or cyclin B–CDK1 shed light on the regulation of chromosome separation during the cell cycle.

Zhang et al. identify a nuclear role for the glycolytic enzyme TPI1 in connecting nutrient status and cell cycle status to global histone acetylation.

The molecular mechanism governing the destruction of key cell-cycle proteins, D-type cyclins, has been elucidated. This mechanism might underlie the lack of response of some human tumours to an inhibitor treatment.

Rosendo-Pineda et al. discover that N-methyl-D-aspartate receptors (NMDAR) mediate transient calcium entry in mitosis, dependent on phosphorylation of NMDAR by Cyclin B1/CDK1. They also find that phosphorylation-mimicking mutants of NMDAR cause mitotic defects, suggesting that precise control of NMDAR-mediated calcium entry is needed for proper mitosis.

The decision of whether and when a cell divides is tightly controlled. Here, the authors show in yeast that there is a multi-step competition between different phosphorylation states and sites in the S phase CDK-Sic1 complex, which controls Sic1 degradation and coordinates the precise timing of the G1/S transition.

Event-driven acquisition uses neural-network-based recognition of specific biological events to trigger switching between slow and fast super-resolution imaging, enriching the capture of interesting events with high spatiotemporal resolution.

Single-cell RNA-sequencing technology gives access to cell cycle dynamics without externally perturbing the cell. Here the authors present DeepCycle,a robust deep learning method to infer the cell cycle state in single cells from scRNA-seq data.

HaloTag variants offer distinct brightness and fluorescence lifetimes compared with HaloTag7 when labeled with rhodamines. These variants were used for multiplexed imaging with a single fluorophore and to create lifetime-based cell cycle indicators.

To enhance the accuracy of CRISPR-Cas9 editing, Matsumoto et al have fused the anti-CRISPR protein AcrIIA4 with Cdt1, a protein that is degraded in S and G₂, the phases of the cell cycle where homology-directed repair (HDR) dominates. This leads to an increase in HDR and in on-target editing, illustrating the feasibility of the approach.

CDK2 can drive the proliferation of cancer cells. Here, the authors screened for a non-ATP competitive inhibitor of the CDK2/cylinA complex and find that Homoharringtonine can disrupt the complex and promote the degradation of CDK2.

Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.

Gaglia, Kabraji and colleagues quantify cell cycle markers in single cells to define the spatial distribution of proliferation in tumours. They define metrics that capture clinically significant features of cancer proliferation.

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6, regulators of the cell cycle, favours the growth and survival of several cancer types. Owing to this, CDK4 and CDK6 inhibitors were developed and are currently approved for the treatment of advanced hormone receptor-positive breast cancer. This Review describes how we are only now beginning to fully understand their mechanisms of action and provides a new framework for conceptualizing their activity, which might enable expansion of the clinical opportunities of these agents.

Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer.

This Review discusses our current understanding of cell cycle regulation, the functions of cell cycle checkpoints and how disruption of these finely tuned mechanisms is associated with cancer. Insights into these regulatory mechanisms are creating new opportunities for the treatment of cancer.

Clinical CDK4/6 inhibitors are used and tested to treat a variety of cancer types. Here, the authors identify that these drugs work in two ways, a known catalytic role to inhibit kinase activity and a newly discovered noncatalytic role to displace CDK inhibitor p21 from CDK4 but not CDK6 complexes.

Poulikakos and colleagues demonstrate that thermostable CDK6 complexes promote resistance to therapeutic targeting of CDK4/6 in cancer.

Goel and colleagues show that CDK4/6 inhibition induces global chromatin changes mediated by AP-1 factors, which mediate key biological and clinical effects in breast cancer.

Oncogenic cell growth and proliferation rely on aberrant activation of metabolic pathways, such as glucose fermentation, resulting in elevated cytosolic pH. Koch et al. implicate increased cytosolic pH as a driver for cell proliferation through the transcriptional activation of cyclin D1.