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A fast-acting lipid checkpoint in G1 prevents mitotic defects
Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass. Here, authors identify a lipid checkpoint in G1 phase that prevents cells from starting the cell cycle if lipid synthesis is low, thereby preventing mitotic defects.
- Marielle S. Köberlin
- , Yilin Fan
- & Tobias Meyer
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Article
| Open Access
Ultrastructure of macromolecular assemblies contributing to bacterial spore resistance revealed by in situ cryo-electron tomography
Bacterial endospores are among the most resilient forms of life. Here, authors reveal ultrastructural details of the spore chromosome and the multiprotein, multilayered extracellular coat, shedding light on mechanisms contributing to spore resistance.
- Elda Bauda
- , Benoit Gallet
- & Cecile Morlot
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| Open Access
Characterization of nucleolar SUMO isopeptidases unveils a general p53-independent checkpoint of impaired ribosome biogenesis
Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.
- Judith Dönig
- , Hannah Mende
- & Stefan Müller
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| Open Access
Non-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity
Cyclin-dependent kinases (CDK4/6) play a crucial role in initiating cell growth. Here, Zhang et al. unveil a mechanism that bypasses CDK4/6, shedding light on an alternative pathway of cell-cycle initiation and quiescence maintenance.
- Mimi Zhang
- , Sungsoo Kim
- & Hee Won Yang
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| Open Access
HDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice
Although accumulating evidence indicates that epithelial cell cycle G2/M arrest is involved in kidney fibrosis, the underlying mechanism remains unclear. Here, the authors show that HDAC9 is upregulated in the fibrotic kidney and promotes epithelial cell cycle arrest in G2/M by regulating STAT1.
- Yang Zhang
- , Yujie Yang
- & Fan Yi
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Article
| Open Access
The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex
The formation of the mitotic checkpoint complex requires an intricate spatial coordination amongst the proteins Bub1, Mad1, Cdc20, and Mad2. Chen et al show that a structural flexibility in Mad1 plays an essential role in achieving this coordination.
- Chu Chen
- , Valentina Piano
- & Ajit P. Joglekar
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Article
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Non-canonical functions of SNAIL drive context-specific cancer progression
SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.
- Mariel C. Paul
- , Christian Schneeweis
- & Dieter Saur
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| Open Access
G1/S restriction point coordinates phasic gene expression and cell differentiation
Somatic cells display phasic gene expression with compartmentalized gene expression during the cell cycle, while pluripotent cells lack phasic expression. Here, the authors describe a pathway linking microRNA regulation of the G1/S restriction point with phasic gene expression and cell differentiation during mammalian development.
- Brian DeVeale
- , Leqian Liu
- & Robert Blelloch
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| Open Access
The NUCKS1-SKP2-p21/p27 axis controls S phase entry
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.
- Samuel Hume
- , Claudia P. Grou
- & Grigory L. Dianov
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CENP-V is required for proper chromosome segregation through interaction with spindle microtubules in mouse oocytes
Chromosome segregation is essential to avoid aneuploidy, yet in mammalian oocytes it progressively fails in an age-dependent manner. Here the authors identify CENP-V as a microtubule binding and bundling protein crucial to faithful oocyte meiosis, and present Cenp-V−/− oocytes as revealing age-dependent weakening of the spindle assembly checkpoint.
- Dalileh Nabi
- , Hauke Drechsler
- & Mariola Chacón
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Article
| Open Access
p107 mediated mitochondrial function controls muscle stem cell proliferative fates
The connection between cell cycle, metabolic state and mitochondrial activity is unclear. Here, the authors show that p107 represses mitochondrial transcription and ATP output in response to glycolytic byproducts, causing metabolic control of the cell cycle rate in myogenic progenitors.
- Debasmita Bhattacharya
- , Vicky Shah
- & Anthony Scimè
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| Open Access
Surveillance of cohesin-supported chromosome structure controls meiotic progression
Meiosis-specific cohesins and the synaptonemal complex are essential for meiotic chromosome structure and function. Here the authors show that continued surveillance of these chromosome structures controls meiotic progression by regulating CHK-2, a master regulator of pairing and recombination.
- Maikel Castellano-Pozo
- , Sarai Pacheco
- & Enrique Martinez-Perez
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| Open Access
Proline-rich protein PRR19 functions with cyclin-like CNTD1 to promote meiotic crossing over in mouse
Crossing over is a critical process during meiosis, although the regulation of this process still remains somewhat elusive. Here, the authors show that PRR19 partners with CNTD1 to enable formation of crossover-specific recombination complexes in mouse germ cells.
- Anastasiia Bondarieva
- , Kavya Raveendran
- & Attila Tóth
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The RepID–CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation
The spindle assembly checkpoint (SAC) safeguards chromosome segregation by regulating the anaphase promoting complex/cyclosome (APC/C), allowing chromosomes to correctly attach to mitotic spindles. Here the authors reveal a role for Cullin–RING ubiquitin ligase complex 4 (CRL4) in regulating metaphase to anaphase transition via BUB3 degradation.
- Sang-Min Jang
- , Jenny F. Nathans
- & Mirit I. Aladjem
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DNA double-strand breaks in telophase lead to coalescence between segregated sister chromatid loci
The mechanism regulating DNA repair in late anaphase or telophase is not yet clear. Here authors reveal that DNA double strand breaks in telophase causes a partial reversal of sister chromosome segregation which could create an opportunity of using the sister for repair in telophase.
- Jessel Ayra-Plasencia
- & Félix Machín
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| Open Access
APC/CCDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression
Ribose-5-phosphate (R5P) is required for DNA synthesis, but how this is regulated during cell cycle progression is unclear. Here the authors report that the cell cycle regulator APC/C-CDH1 synchronizes cell cycle progression with R5P-derived DNA synthesis by controlling TKTL1 stability
- Yang Li
- , Cui-Fang Yao
- & Jian-Yuan Zhao
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| Open Access
Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling
The mechanisms promoting insulin resistance at the receptor level are poorly understood. Here, Choi et al. show that mitotic proteins and the SHP2-MAPK pathway regulate receptor endocytosis and insulin signaling feedback, identifying a potential role for SHP2 inhibitors to treat diabetes.
- Eunhee Choi
- , Sotaro Kikuchi
- & Hongtao Yu
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| Open Access
Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction
Protein homeostasis maintenance (proteostasis) is critical for cell function, but declines during aging. Here the authors detail a proteostatic checkpoint in Drosophila intestinal stem cells coordinating cell cycle arrest with protein aggregate clearance, along with its role in aging related intestinal dysfunction.
- Imilce A. Rodriguez-Fernandez
- , Yanyan Qi
- & Heinrich Jasper
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| Open Access
Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase
Cell rounding at mitosis is driven by cortical tension and maintained through metaphase, although the mechanism is unknown. Here, the authors demonstrate that Cdk1 phosphorylation of DIAPH1 is required for both cortical tension maintenance and inactivation of the spindle assembly checkpoint.
- Koutarou Nishimura
- , Yoshikazu Johmura
- & Makoto Nakanishi
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| Open Access
TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC
The mitotic checkpoint complex (MCC) is assembled during both mitosis and interphase. Here, the authors use auxin-inducible degron tags to rapidly degrade TRIP13 and find that mitotic exit requires MCC disassembly by TRIP13-catalyzed removal of Mad2 or APC1-driven ubiquitination of Cdc20.
- Dong Hyun Kim
- , Joo Seok Han
- & Don W. Cleveland
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| Open Access
ATR is a multifunctional regulator of male mouse meiosis
ATR kinase is required for meiosis in non-mammalian model organisms. Here the authors demonstrate, using a tissue-specific knockout approach, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis.
- Alexander Widger
- , Shantha K. Mahadevaiah
- & James M.A. Turner
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Article
| Open Access
ATR is required to complete meiotic recombination in mice
ATR kinase is required for meiosis in non-mammalian model organisms. Here the authors demonstrate, using a hypomorphic Atr mutation and chemical inhibition, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis.
- Sarai Pacheco
- , Andros Maldonado-Linares
- & Ignasi Roig
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| Open Access
BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage
Loss of BRCA2 leads to cancer formation. Here, the authors use an insertional mutagenesis approach and identify a multiprotein complex consisting of BRE, USP7 and CDC25A that can support the survival of BRCA2-deficient cells.
- Kajal Biswas
- , Subha Philip
- & Shyam K. Sharan
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| Open Access
Multiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts
During S phase of the cell cycle, transcription and replication need to be coordinated in order to avoid conflicts leading to potential genomic instability. Here, the authors find that Mrc1 integrates signals from different kinases to regulate replication during unscheduled transcription events.
- Alba Duch
- , Berta Canal
- & Francesc Posas
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Article
| Open Access
Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression. Here the authors show that CHK1 loss or chemical inhibition impacts on normal B cell development, lymphomagenesis and cancer cell survival.
- Fabian Schuler
- , Johannes G. Weiss
- & Andreas Villunger
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Article
| Open Access
A programmed cell division delay preserves genome integrity during natural genetic transformation in Streptococcus pneumoniae
In Streptococcus pneumoniae, competence for genetic transformation is accompanied by a pause in growth. Here, Bergé et al. show that this pause is linked to the cell cycle via at least two pathways that impair peptidoglycan synthesis and preserve genomic integrity during transformation.
- Matthieu J. Bergé
- , Chryslène Mercy
- & Nathalie Campo
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| Open Access
EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop
The histone methyltransferase EZH2 silences genes by generating H3K27me3 marks. Here the authors use a 3D GC organoid and show EZH2 mediates germinal centre (GC) formation through epigenetic silencing of CDKN1A and release of cell cycle checkpoints.
- Wendy Béguelin
- , Martín A. Rivas
- & Ari M. Melnick
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| Open Access
Arabidopsis R1R2R3-Myb proteins are essential for inhibiting cell division in response to DNA damage
Inhibition of cell division maintains genome integrity in response to DNA damage. Here Chen et al. propose that DNA damage causes cell cycle arrest in the Arabidopsis root via Rep-MYB transcription factor-mediated repression of G2/M-specific gene expression in response to reduced cyclin-dependent kinase activity.
- Poyu Chen
- , Hirotomo Takatsuka
- & Masaaki Umeda
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| Open Access
Yeast Cip1 is activated by environmental stress to inhibit Cdk1–G1 cyclins via Mcm1 and Msn2/4
A G1 cell cycle regulatory kinase Cip1 has been identified in budding yeast but how this is regulated is unclear. Here the authors identify cell cycle (Mcm1) and stress-mediated (Msn 2/4) transcription factors as regulating Cip1, causing stress induced CDK inhibition and delay in cell cycle progression.
- Ya-Lan Chang
- , Shun-Fu Tseng
- & Shu-Chun Teng
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| Open Access
Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling
The spindle assembly checkpoint ensures correct chromosome segregation and relies on kinetochore localization of the Bub1 and Mad1/Mad2 checkpoint proteins. Here the authors show that main function of Bub1 is to position Mad1 close to KNL1 MELT repeats in human cells.
- Gang Zhang
- , Thomas Kruse
- & Jakob Nilsson
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Article
| Open Access
Inner centromere localization of the CPC maintains centromere cohesion and allows mitotic checkpoint silencing
Precise chromosome segregation during mitosis requires coordination of stable chromosome bi-orientation with anaphase onset, however the underlying mechanism is not clear. Here the authors show that inner centromere localization of the chromosomal passenger complex maintains centromeric cohesion on bi-oriented chromosomes and allows mitotic checkpoint silencing.
- Rutger C. C. Hengeveld
- , Martijn J. M. Vromans
- & Susanne M. A. Lens
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| Open Access
Temporal and compartment-specific signals coordinate mitotic exit with spindle position
The mitotic exit network (MEN) triggers mitotic exit and can be blocked by the spindle position checkpoint (SPOC). Here the authors show that SPOC kinase Kin4 counterbalances MEN activation by the Cdc fourteen early anaphase release (FEAR) network in the mother cell and that in the absence of FEAR mitotic exit requires daughter cell-confined factors.
- Ayse Koca Caydasi
- , Anton Khmelinskii
- & Gislene Pereira
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| Open Access
CDK1 phosphorylates WRN at collapsed replication forks
End-resection of double strand DNA breaks is essential for pathway choice between non-homologous end-joining and homologous recombination. Here the authors show that phosphorylation of WRN helicase by CDK1 is essential for resection at replication-related breaks.
- Valentina Palermo
- , Sara Rinalducci
- & Pietro Pichierri
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| Open Access
Hypersensitivity to DNA damage in antephase as a safeguard for genome stability
The DNA damage response induces a reversible arrest at different cell cycle stages. Here the authors find that loss of the APC/C inhibitor Emi1 in antephase (late G2) results in hypersensitivity to DNA damage and cell cycle exit at DNA damage levels that induce a reversible arrest in early G2.
- Femke M. Feringa
- , Lenno Krenning
- & René H. Medema
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| Open Access
Clks 1, 2 and 4 prevent chromatin breakage by regulating the Aurora B-dependent abscission checkpoint
Cells delay completion of cytokinesis when chromatin is trapped at the intercellular bridge. Here, Petsalaki and Zachos report that Cdc-like kinases (Clks) 1, 2 and 4 localize to the midbody and phosphorylate the mitotic kinase Aurora B, imposing the abscission checkpoint to prevent premature abscission and chromatin breakage.
- Eleni Petsalaki
- & George Zachos
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| Open Access
Interphase APC/C–Cdc20 inhibition by cyclin A2–Cdk2 ensures efficient mitotic entry
The Anaphase Promoting Complex/Cyclosome (APC/C) and its co-activator Cdc20 regulate mitotic progression, but both are also present in interphase. Here Hein and Nilsson show that Cyclin A2–CDK2 phosphorylates Cdc20 to inhibit APC/C–Cdc20 activity during this cell cycle phase to promote mitotic entry.
- Jamin B. Hein
- & Jakob Nilsson
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Article
| Open Access
Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2
The spindle assembly checkpoint relies on the accumulation of Mad1-Mad2 at kinetochores, but the mechanism of regulation is not known. Here Zhou et al. show that the centrosomal protein Cep57 interacts with the kinetochore proteins Mis12 and Mad1, and regulates the recruitment of Mad1/Mad2 to kinetochores.
- Haining Zhou
- , Tianning Wang
- & Jianguo Chen
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Article
| Open Access
Kinetochore–microtubule attachment is sufficient to satisfy the human spindle assembly checkpoint
The spindle assembly checkpoint protects against premature chromosome segregation during mitosis but it is not known whether microtubule attachment to the kinetochore, or force generated from this interaction, is being monitored. Here the authors uncouple these processes and show that microtubule attachment is sufficient to satisfy the checkpoint.
- Banafsheh Etemad
- , Timo E. F. Kuijt
- & Geert J. P. L. Kops
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| Open Access
Stable kinetochore–microtubule attachment is sufficient to silence the spindle assembly checkpoint in human cells
The spindle assembly checkpoint prevents mitotic progression when chromosomes are not properly attached to the mitotic spindle. Here Tauchman et al.show that stable microtubule attachment to the kinetochore, and not tension generated from this interaction, is sufficient to silence the checkpoint.
- Eric C. Tauchman
- , Frederick J. Boehm
- & Jennifer G. DeLuca
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Article
| Open Access
Spindle assembly checkpoint inactivation fails to suppress neuroblast tumour formation in aurA mutant Drosophila
Drosophila aurA mutants develop brain tumours which are associated with defective mitotic spindle assembly. Caous et al. show that these mutants are surprisingly insensitive to tumour-suppressive spindle assembly checkpoint inactivation, due to a checkpoint-independent delay in cyclin B degradation.
- Renaud Caous
- , Aude Pascal
- & Régis Giet
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Article
| Open Access
DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age
DNA damage in mammalian oocytes can lead to infertility and developmental disorders. Here Marangos et al.show that the spindle assembly checkpoint responds to DNA damage by arresting oocytes in metaphase I, and this checkpoint becomes compromised as mice age.
- Petros Marangos
- , Michelle Stevense
- & John Carroll
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Article
| Open Access
Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function
Cohesion is associated with many forms of cancer. De Lange et al. show that such cohesion defects can sensitise cells to apoptosis in response to a new APC/C ubiquitin ligase inhibitor, by prolonging mitotic arrest and checkpoint activation due to cohesion fatigue.
- Job de Lange
- , Atiq Faramarz
- & Rob M. F. Wolthuis
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| Open Access
TORC1 controls G1–S cell cycle transition in yeast via Mpk1 and the greatwall kinase pathway
The target of rapamycin complex 1 (TORC1) pathway couples nutrient availability with cell growth and division by destabilizing the cyclin-dependent kinase (CDK) inhibitor Sic1. Here the authors show that TORC1 downregulation leads to stabilization of Sic1 via phosphorylation by the MAP kinase Mpk1 and inhibition of dephosphorylation via the greatwall kinase pathway.
- Marta Moreno-Torres
- , Malika Jaquenoud
- & Claudio De Virgilio
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Article
| Open Access
An actin-dependent spindle position checkpoint ensures the asymmetric division in mouse oocytes
In mammalian oocytes, the meiotic spindle is assembled close to the centre of the cell and relocates to the cell periphery prior to chromosome segregation. Here Metchat et al. show that anaphase is delayed until the spindle is positioned close to the cell cortex, providing evidence for a spindle position checkpoint.
- Aïcha Metchat
- , Manuel Eguren
- & Jan Ellenberg
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| Open Access
Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells
CENP-E regulates chromosome alignment during mitosis to distribute chromosomes equally into daughter cells. Here, the authors show that CENP-E inhibition causes p53-mediated post-mitotic apoptosis in tumours where the spindle assembly checkpoint is compromised, suggesting that CENP-E is a therapeutic target for these cancers.
- Akihiro Ohashi
- , Momoko Ohori
- & Kentaro Iwata
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Article
| Open Access
Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
FOXM1, a transcription factor with roles in cell cycle progression, is highly expressed in the majority of solid tumours. Here the authors show that FOXM1 is an ideal therapeutic target in B-cell acute lymphoblastic leukaemia (ALL) due to its dispensability for normal B-cell development.
- Maike Buchner
- , Eugene Park
- & Markus Müschen
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Article
| Open Access
Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements
Homologous recombination can overcome replication fork inactivation, but this can cause gross chromosomal rearrangements. Here, the authors show that DNA damage and intra-S phase checkpoints are blind to chromosome rearrangement in the first cell cycle, and are only induced in the second cell cycle.
- Saed Mohebi
- , Ken’Ichi Mizuno
- & Johanne M. Murray
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WT1 interacts with MAD2 and regulates mitotic checkpoint function
The transcription factor WT1 can act as either a tumour suppressor or an oncogene by regulating gene expression. Shandilya et al. show that WT1 also directly activates the spindle assembly checkpoint by binding the checkpoint protein MAD2 to delay anaphase and promote chromosomal stability.
- Jayasha Shandilya
- , Eneda Toska
- & Stefan G. E. Roberts
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Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint
During cell division, a single chromosome that lacks attachment to microtubules is sufficient to delay chromosome segregation. Chen and Liu construct a model demonstrating that the transport of regulators along microtubules may explain the remarkable sensitivity and robustness of this checkpoint.
- Jing Chen
- & Jian Liu
Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation