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| Open AccessNon-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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Article
| Open AccessCENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly
It is unknown how the kinetochore fibrous corona is disassembled. Here, the authors reveal that Aurora A and B kinases-mediated phosphorylation activates CENP-E, which is essential to prevent the premature removal of corona proteins by dynein.
- Susana Eibes
- , Girish Rajendraprasad
- & Marin Barisic
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| Open AccessCENP-F-dependent DRP1 function regulates APC/C activity during oocyte meiosis I
Spindle assembly checkpoint controls anaphase onset and guarantees appropriate chromosome segregation. Here, the authors report that dynamin-related protein 1 is recruited to kinetochores by CENP-F to regulate metaphase-to-anaphase transition by controlling APC/C activity in mouse oocyte meiosis
- Cheng-Jie Zhou
- , Xing-Yue Wang
- & Cheng-Guang Liang
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Article
| Open AccessAirway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis
The functional role of airway basal cells has not been comprehensively studied in idiopathic pulmonary fibrosis (IPF). Here, the authors show that airway basal cells of IPF patients display a distinct phenotype, are profibrotic if transplanted to mice and that fibrosis can be ameliorated by Src iinhibitors.
- Benedikt Jaeger
- , Jonas Christian Schupp
- & Antje Prasse
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| Open AccessUbiquitination of CLIP-170 family protein restrains polarized growth upon DNA replication stress
The microtubule plus-end tracking protein Tip1 regulates microtubule dynamics and polar growth in fission yeast. Here the authors link the ubiquitination of Tip1 by ubiquitin ligase Dma1 to polarized growth inhibition upon DNA replication stress.
- Xi Wang
- , Fan Zheng
- & Quan-wen Jin
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Article
| Open AccessStructure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse
NKR-P1 is an inhibitory receptor on the surface of natural killer cells, and its engagement with the ligand LLT1 on activated monocytes and B cells triggers NK cell self-tolerance and other immunological processes. Here authors set up a comprehensive, structure-based model of NKR-P1-LLT1 interaction that involves NKR-P1 homodimer formation and subsequent bridging of two LLT1 molecules.
- Jan Bláha
- , Tereza Skálová
- & Ondřej Vaněk
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Article
| Open AccessATR inhibition enables complete tumour regression in ALK-driven NB mouse models
Effective therapeutic options are still needed in neuroblastoma treatment. Here, the authors, through a comprehensive proteomics analysis, identify ATR as a potential therapeutic target of neuroblastoma and demonstrate the efficacy of the ATR inhibitor BAY1895344 in combination with the ALK tyrosine kinase inhibitor lorlatinib.
- Joanna Szydzik
- , Dan E. Lind
- & Ruth H. Palmer
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Article
| Open AccessEndothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin
The vascular endothelium contributes to metabolic regulation, however, the underlying mechanisms are not fully understood. Here the authors show that endothelial low-density lipoprotein receptor-related protein 1 regulates glucose homeostasis via osteocalcin expression.
- Hua Mao
- , Luge Li
- & Xinchun Pi
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Article
| Open AccessAltered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity
How normal cells proliferate without CDK4 and CDK6, two cancer-driving kinases, remains unclear. Here, the authors show that without CDK4/6 activity, cells start the cell cycle with a different signaling order and commitment point, revealing unexpected flexibility in cell-cycle entry mechanisms.
- Chad Liu
- , Yumi Konagaya
- & Tobias Meyer
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Article
| Open AccessATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration
The nucleus is a mechanically stiff organelle of the cell and the DNA damage response protein ATR can localize to the nuclear envelope upon mechanical stress. Here, the authors show that ATR may contribute to the integrity of the nuclear envelope and may play a role in cell migration.
- Gururaj Rao Kidiyoor
- , Qingsen Li
- & Marco Foiani
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| Open AccessThe Rad53CHK1/CHK2-Spt21NPAT and Tel1ATM axes couple glucose tolerance to histone dosage and subtelomeric silencing
The relationship between DNA damage response (DDR) and regulation of the tolerance to glucose restriction is currently unclear. Here the authors reveal that maintaining a physiological level of histones by Rad53-Spt21 is necessary for glucose tolerance via multiple parallel pathways, including derepression of subtelomeric genes and acetyl-coA regulation by histone acetylation.
- Christopher Bruhn
- , Arta Ajazi
- & Marco Foiani
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Article
| Open AccessRUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point
The transcription factor RUNX3 plays a key role in the restriction point of cell cycle. Here the authors showed that RUNX3 binds and opens chromatin structure of restriction point associated genes, by sequential recruitment of chromatin remodeling complex, transcription complex and cell cycle regulators.
- Jung-Won Lee
- , Da-Mi Kim
- & Suk-Chul Bae
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| Open AccessQuantitative sensing and signalling of single-stranded DNA during the DNA damage response
DNA damage triggers checkpoint signalling mechanisms. Here the authors reveal differential phosphorylation of targets of the Mec1-Ddc2 checkpoint kinase by analyzing the effect of quantitatively different ssDNA signals.
- Susanne C. S. Bantele
- , Michael Lisby
- & Boris Pfander
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Article
| Open AccessHDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130
Checkpoint kinases control cell cycle progression via the regulation of many key regulators. Here the authors demonstrate how HDAC1 and HDAC2 modulate checkpoint kinase signalling via the suppression of PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2.
- Anja Göder
- , Claudia Emmerich
- & Oliver H. Krämer
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Article
| Open AccessATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1
ATR kinase activity is essential for slowing replication forks and preventing DNA replication in cells with DNA damage. Here the authors show that ATR inhibition leads to Cdc7 phosphorylation of GINS, leading to origin firing.
- Tatiana Moiseeva
- , Brian Hood
- & Christopher J. Bakkenist
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Article
| Open AccessAUNIP/C1orf135 directs DNA double-strand breaks towards the homologous recombination repair pathway
DNA double strand breaks can be repaired by homology-independent or homology-directed mechanisms. The choice between these pathways is a key event for genomic stability maintenance. Here the authors identify and characterize AUNIP, as a factor involved in tilting the balance towards homology repair.
- Jiangman Lou
- , Hongxia Chen
- & Jun Huang
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Article
| Open AccessTemporal 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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Article
| Open AccessmiR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint
Resistance to chemotherapy occurs in many ovarian cancer cases. Here, the authors show that mir-424(322) expression restores the sensitivity of ovarian cancer cells to chemotherapy by blocking the PD-L1 immune checkpoint, and find that combining immunotherapy and chemotherapy has a synergistic effect.
- Shaohua Xu
- , Zhen Tao
- & Ke Chen
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| Open AccessThe Bub1–Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation
The mitotic checkpoint complex (MCC) inhibits the anaphase-promoting complex (APC/C) bound to Cdc20 in response to spindle defects. Here, the authors show that Bub1-Plk1-mediated phosphorylation of Cdc20 constitutes a parallel, non-redundant APC/C-inhibitory mechanism in addition to MCC activity.
- Luying Jia
- , Bing Li
- & Hongtao Yu
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Article
| Open AccessBub1 autophosphorylation feeds back to regulate kinetochore docking and promote localized substrate phosphorylation
Bub1 kinase phosphorylates histone H2A-T120 at the centromere to recruit shugoshin proteins and promote sister chromatid cohesion during mitosis. Here the authors show that Bub1 autophosphorylation on T589 influences Bub1 dynamics at the kinetochore and restricts H2A-T120 phosphorylation to centromeres.
- Adeel Asghar
- , Audrey Lajeunesse
- & Sabine Elowe
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Article
| Open AccessDistinct domains in Bub1 localize RZZ and BubR1 to kinetochores to regulate the checkpoint
The spindle assembly checkpoint (SAC) depends on the recruitment of specific protein complexes to the kinetochore. Here Zhang et al. show that Bub1 recruits the RZZ complex and BubR1 to the kinetochore, and loss of the BubR1 binding sequence enhances checkpoint activity suggesting both SAC activating and silencing roles.
- Gang Zhang
- , Tiziana Lischetti
- & Jakob Nilsson
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Borealin dimerization mediates optimal CPC checkpoint function by enhancing localization to centromeres and kinetochores
Borealin is a subunit of the chromosomal passenger complex that prevents premature mitosis before spindle assembly is complete. Bekier et al.show that Borealin mediates recruitment of this complex to both kinetochores and centromeres via distinct mechanisms, both of which depend on Borealin dimerization.
- Michael E. Bekier
- , Travis Mazur
- & William R. Taylor
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The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing
Kinetochores that fail to form bipolar attachments to the mitotic spindle delay chromosome segregation by BubR1 mediated inhibition of Cdc20. Lischetti et al.show that BubR1 recruits Cdc20 to the kinetochore via a domain that mediates both checkpoint activation and silencing.
- Tiziana Lischetti
- , Gang Zhang
- & Jakob Nilsson
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ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets
The tumour suppressor ARF regulates p53 levels; however, in contrast to p53, ARF has not been implicated in the response to DNA damage. In this study, Carlos et al.show that single-stranded DNA formed in BRCA2-null cells triggers a DNA damage response leading to the activation of ARF and senescence.
- Ana Rita Carlos
- , Jose Miguel Escandell
- & Madalena Tarsounas
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Article |
FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress
DNA replication stress promotes genome instability and cell death. Here Fugger et al.describe how FBH1, via its helicase activity, is required to eliminate cells with excessive DNA replication stress, through the generation of MUS81-induced DNA double-strand breaks.
- Kasper Fugger
- , Wai Kit Chu
- & Claus Storgaard Sørensen
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| Open AccessFcp1-dependent dephosphorylation is required for M-phase-promoting factor inactivation at mitosis exit
Cyclin B-dependent kinase 1, the M-phase-promoting factor, is precisely activated and inactivated to control mitosis. In this study, Fcp1—the RNA polymerase II-carboxy-terminal domain phosphatase—is identified as a phosphatase required to inactivate the M-phase-promoting factor and promote mitosis exit.
- Roberta Visconti
- , Luca Palazzo
- & Domenico Grieco
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| Open AccessAurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis
Mitotic exit is controlled by a cell division checkpoint that prevents premature degradation of cyclin B by the anaphase-promoting complex. Saurinet al. show that Aurora B directly regulates timely establishment of this checkpoint by facilitating activation of Mps1 kinase at unattached kinetochores.
- Adrian T. Saurin
- , Maike S. van der Waal
- & Geert J.P.L. Kops