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TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation
cGAS/STING activation is linked to the induction of anti-tumor immune responses. Here the authors report a role for the deubiquitinating enzyme TRABID in regulating mitotic cell division and suppressing anti-tumor immunity, suggesting that TRABID inhibition induces micronuclei and activates cGAS/STING pathway.
- Yu-Hsuan Chen
- , Han-Hsiun Chen
- & Ruey-Hwa Chen
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Article
| 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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Comment
| Open Access
Structural insights into how augmin augments the mitotic spindle
Cell division critically requires amplification of microtubules (MTs) in the bipolar mitotic spindle. This relies on the filamentous augmin complex that enables MT branching. Studies by Gabel et al., Zupa et al. and Travis et al. describe consistent integrated atomic models of the extraordinarily flexible augmin complex. Their work prompts the question: what is this flexibility really needed for?
- Szymon W. Manka
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Integrated model of the vertebrate augmin complex
Many microtubules in the mitotic spindle are made through microtubule branching. Here, the authors report a structural model of the augmin complex and insights into its role in microtubule branching.
- Sophie M. Travis
- , Brian P. Mahon
- & Sabine Petry
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Distinct dynein complexes defined by DYNLRB1 and DYNLRB2 regulate mitotic and male meiotic spindle bipolarity
Male meiosis relies on canonical centrosomes for spindle formation, but how this differs from acentrosomal oocyte meiosis is unclear. Here they show that spindle formation in sperm relies on DYNLRB2, similar to the activity of DYNLRB1 in mitotic cells.
- Shuwen He
- , John P. Gillies
- & Hiroki Shibuya
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Article
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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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Short-term molecular consequences of chromosome mis-segregation for genome stability
Chromosomal instability leads to aneuploidy, a state of karyotype imbalance. By inducing controlled chromosome mis-segregation, Santaguida and colleagues show that aneuploidy can also instigate chromosomal instability.
- Lorenza Garribba
- , Giuseppina De Feudis
- & Stefano Santaguida
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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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Article
| Open Access
DNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation
RECQ4 mutations contribute to multiple developmental diseases and tumorigenesis. Here the authors describe how a highly oncogenic RECQ4 mutation alters the control of DNA synthesis, leading to abnormal DNA content and cell growth.
- Xiaohua Xu
- , Chou-Wei Chang
- & Yilun Liu
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Article
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A single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury
The transcriptional network in TMJ disc development and injury remains poorly characterized. Here they generate a scRNA-seq atlas of mouse TMJ disc, and identify the resident progenitor population and how its transcriptional reprogramming contributes to disc repair.
- Ruiye Bi
- , Qing Yin
- & Songsong Zhu
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Article
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Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells
DNA replication stress can generate under-replicated DNA regions which is fixed by an atypical form of DNA repair synthesis in mitosis (MiDAS). Here the authors show that translesion and replicative DNA polymerases cooperate via the POLD3 subunit to complete MiDAS in human cells.
- Wei Wu
- , Szymon A. Barwacz
- & Ying Liu
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Article
| Open Access
Master mitotic kinases regulate viral genome delivery during papillomavirus cell entry
Human papillomavirus (HPV) coopts mitosis for nuclear entry by tethering the viral DNA to mitotic chromosomes, a process facilitated by the viral minor capsid protein L2. Here, Rizzato et al. show that L2 contains conserved phosphorylation motifs within the chromosome-binding region and provide evidence that host master mitotic kinases CDK1 and PLK1 sequentially mediate phosphorylation of L2 at mitosis onset to allow timely tethering of viral DNA to mitotic chromosomes.
- Matteo Rizzato
- , Fuxiang Mao
- & Mario Schelhaas
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Article
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Phosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1
Many kinases phosphorylate proteins on multiple sites, however in most cases it is not known which sites are functionally important. Here, the authors describe a high-throughput approach to quantitatively evaluate the contribution of each phosphosite within a multisite phosphorylated domain.
- Michelle M. Conti
- , Rui Li
- & Jennifer A. Benanti
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Article
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Annexin A1 is a polarity cue that directs mitotic spindle orientation during mammalian epithelial morphogenesis
Regulation of oriented cell divisions during development is important to position daughter cells and build a structured and functional tissue. Here the authors show that Annexin A1 is a key polarity protein that regulates planar orientation of the cell division axis to guide mammary epithelial morphogenesis.
- Maria Fankhaenel
- , Farahnaz S. Golestan Hashemi
- & Salah Elias
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Article
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Functional crosstalk between the cohesin loader and chromatin remodelers
Chromatin remodelers direct the cohesin loader to nucleosome depleted regions where cohesin accesses chromosomes. Muñoz et al. now show that the cohesin loader in turn is a biochemical activator of a chromatin remodeler, helping to clear nucleosomes
- Sofía Muñoz
- , Andrew Jones
- & Frank Uhlmann
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Article
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CENP-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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DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal
How and whether histone modifications regulate distinct gene networks remains insufficiently understood. Here Cattaneo et al show that DOT1L catalyzed H3K79me2 regulates fetal chamber-specific gene expression and neonatal cardiomyocyte cell cycle withdrawal to coordinate heart development.
- Paola Cattaneo
- , Michael G. B. Hayes
- & Sylvia M. Evans
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Kinetochore- and chromosome-driven transition of microtubules into bundles promotes spindle assembly
Mitotic spindle assembly is not fully understood. This work reveals that kinetochores drive the coarsening of a uniform microtubule array into bundles, which promote spindle formation and chromosome segregation fidelity.
- Jurica Matković
- , Subhadip Ghosh
- & Iva M. Tolić
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Article
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Chromosome segregation fidelity requires microtubule polyglutamylation by the cancer downregulated enzyme TTLL11
The authors show that polyglutamylation of spindle microtubules is essential for error-free chromosome segregation and is mediated through Tubulin Tyrosine Ligase Like 11 (TTLL11), which is found to be frequently downregulated in cancer.
- Ivan Zadra
- , Senda Jimenez-Delgado
- & Isabelle Vernos
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Article
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Cell division drives DNA methylation loss in late-replicating domains in primary human cells
DNA methylation loss has been observed in aging tissues and cancers for decades. Researchers from Van Andel Institute have now provided experimental evidence that this process is directly driven by cell division.
- Jamie L. Endicott
- , Paula A. Nolte
- & Peter W. Laird
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Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.
- Laura J. Grange
- , John J. Reynolds
- & Grant S. Stewart
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Article
| Open Access
Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor
β-TrCP plays an important role in diverse cellular processes such as the cell cycle and inflammation. Here the authors develop a biosensor for β-TrCP activity and use it to investigate β-TrCP dynamics during the cell cycle, and to screen a small-molecule library for β-TrCP activators and inhibitors.
- Debasish Paul
- , Stephen C. Kales
- & Steven D. Cappell
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Article
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Engineered helicase replaces thermocycler in DNA amplification while retaining desired PCR characteristics
PCR is an essential method for the amplification and manipulation of nucleic acids, but the requirement for a thermocycler limits access. Here, authors engineer a helicase to replace the heating step of PCR with enzymatic unwinding, allowing the isothermal amplification of fragments up to 6 kb.
- Momčilo Gavrilov
- , Joshua Y. C. Yang
- & Taekjip Ha
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Article
| Open Access
Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3
Inducible disruption of TET dioxygenases in mouse embryonic stem cells results in chromosome mis-segregation and aneuploidies, due to Khdc3 downregulation suggesting a role for TET enzymes and DNA methylation patterns in maintaining genome stability.
- Romain O. Georges
- , Hugo Sepulveda
- & Anjana Rao
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Article
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Central role of Prominin-1 in lipid rafts during liver regeneration
Bahn et al explore the role of the lipid raft protein Prominin-1 in liver regeneration. They show that Prominin-1 promotes hepatocyte proliferation after acute liver injury by interacting with the signal transducer GP130, confining it to lipid rafts and activating IL-6 signaling pathway and eventual activation of STAT3.
- Myeong-Suk Bahn
- , Dong-Min Yu
- & Young-Gyu Ko
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Article
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Solving the MCM paradox by visualizing the scaffold of CMG helicase at active replisomes
For several decades the MCM2-7 proteins, the core of the DNA replicative helicase, eluded detection at DNA replication sites. Here, the authors solve this conundrum by gene editing, which enables visualization of replication dynamics in living cells.
- Hana Polasek-Sedlackova
- , Thomas C. R. Miller
- & Jiri Lukas
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Article
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Endothelial cell cycle state determines propensity for arterial-venous fate
During blood vessel development, endothelial cells become specified toward arterial or venous fates. Chavkin et al find that distinct endothelial cell cycle states provide windows of opportunity for the molecular induction of arterial or venous fate.
- Nicholas W. Chavkin
- , Gael Genet
- & Karen K. Hirschi
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Article
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Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease
Acute kidney injury is frequent, often fatal and can leave survivors with chronic kidney disease. Here the authors show that tubular cell polyploidy reduces early fatality sustaining residual function but promotes chronic kidney disease, which can be prevented by blocking YAP1
- Letizia De Chiara
- , Carolina Conte
- & Paola Romagnani
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Article
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The augmin complex architecture reveals structural insights into microtubule branching
The formation of branched microtubule networks in mitotic spindles depends on the augmin complex. Zupa, Würtz et al. elucidate the molecular architecture and conformational plasticity of the augmin complex using integrative structural biology, providing structural insights into microtubule branching.
- Erik Zupa
- , Martin Würtz
- & Stefan Pfeffer
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Molecular architecture of the augmin complex
The eight-subunit augmin complex is required to nucleate branching microtubules and create a robust mitotic spindle during cell division. Here, the authors use cryo-EM, crosslinking mass spectrometry, and computational tools to build a structural model of the human augmin complex.
- Clinton A. Gabel
- , Zhuang Li
- & Leifu Chang
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Article
| Open Access
Evolution of longitudinal division in multicellular bacteria of the Neisseriaceae family
Rod-shaped bacteria typically elongate and divide by transverse fission, but a few species are known to divide longitudinally. Here, the authors use genomic, phylogenetic and microscopy techniques to shed light on the evolution of cell shape, multicellularity and division mode within the family Neisseriaceae.
- Sammy Nyongesa
- , Philipp M. Weber
- & Frédéric J. Veyrier
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Article
| Open Access
Evidence for a HURP/EB free mixed-nucleotide zone in kinetochore-microtubules
Microtubules are built from GDP-tubulin lattices with small GTP caps at their plus-ends. Here, the authors reveal that microtubules that attach to kinetochores in mitosis contain, in addition to the GTP-cap and the GDP-lattices, a dynamic micron-sized mixed-nucleotide zone.
- Cédric Castrogiovanni
- , Alessio V. Inchingolo
- & Patrick Meraldi
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Article
| Open Access
PRC1-mediated epigenetic programming is required to generate the ovarian reserve
In humans, the ovarian reserve is maintained over decades by meiotic arrest of oocytes. Here the authors show that Polycomb Repressive Complex 1 (PRC1)-mediated epigenetic programming is essential for formation of ovarian reserve and thus female reproductive lifespan.
- Mengwen Hu
- , Yu-Han Yeh
- & Satoshi H. Namekawa
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Proteomic characterization of the Toxoplasma gondii cytokinesis machinery portrays an expanded hierarchy of its assembly and function
The basal complex is orchestrating Toxoplasma gondii cell division steps. Here, the authors use proximity biotinylation to map the proteome of this contractile ring, identify components acting on its formation, stability and constriction, and reveal bidirectional daughter budding.
- Klemens Engelberg
- , Tyler Bechtel
- & Marc-Jan Gubbels
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Article
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A phylogenetically-restricted essential cell cycle progression factor in the human pathogen Candida albicans
Chromosomal instability caused by cell division errors is associated with antifungal drug resistance in fungal pathogens. Here, Jaitly et al. identify several genes involved in chromosomal stability in Candida albicans, including a phylogenetically restricted gene encoding an essential cell-cycle progression factor.
- Priya Jaitly
- , Mélanie Legrand
- & Kaustuv Sanyal
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Article
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The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis
In this work, CIP2A is discovered as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability.
- Mara De Marco Zompit
- , Mònica Torres Esteban
- & Manuel Stucki
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Article
| Open Access
Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis
Whole-genome doubling (WGD) commonly occurs in many solid tumors. Here the authors use a zebrafish model of melanoma and in vitro models to show that BRAFV600E induces WGD via inhibition of RhoA and cytokinesis failure.
- Revati Darp
- , Marc A. Vittoria
- & Craig J. Ceol
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Article
| Open Access
The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
Long non-coding RNAs (lncRNAs) can contribute to cancers that are driven by Sonic hedgehog (SHH) signaling. Here the authors report that lncRNA HHIP-AS1 stabilises the mRNA of dynein complex 1, thereby, promoting the pro-mitotic effects of SHH-driven tumors.
- Jasmin Bartl
- , Marco Zanini
- & Marc Remke
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Article
| Open Access
Inactivation of the Hippo tumor suppressor pathway promotes melanoma
Activating mutations of BRAF alone are inadequate to drive melanoma formation. Here the authors show that activation of Hippo signalling by oncogenic BRAF represents an additional safeguard to limit BRAF-dependent human melanocyte growth and melanoma formation.
- Marc A. Vittoria
- , Nathan Kingston
- & Neil J. Ganem
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Article
| 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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Article
| Open Access
FANCM promotes class I interfering crossovers and suppresses class II non-interfering crossovers in wheat meiosis
The FANCM helicase functions in limiting crossovers (COs) by unwinding inter-homolog repair intermediates. Here, the authors generate null mutants of fancm in tetraploid and hexaploid wheat and show that FANCM promotes class I interfering COs and suppresses class II noninterfering COs in wheat meiosis.
- Stuart D. Desjardins
- , James Simmonds
- & James D. Higgins
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Article
| Open Access
Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation
Here the authors show that differentiation of haematopoietic stem cells into mature blood cells is primed by cell type-specific transcription factors at the enhancer level during early differentiation, before they confere promoter-driven growth arrest, and activate post-mitotic terminal differentiation.
- Kim Theilgaard-Mönch
- , Sachin Pundhir
- & Bo T. Porse
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Article
| Open Access
Cell cycle gene regulation dynamics revealed by RNA velocity and deep-learning
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.
- Andrea Riba
- , Attila Oravecz
- & Nacho Molina
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Article
| Open Access
Cortical Cyclin A controls spindle orientation during asymmetric cell divisions in Drosophila
The Frizzled/Dishevelled planar cell polarity pathway is involved in mitotic spindle orientation, but how this is coordinated with the cell cycle is unclear. Here, the authors show with Drosophila sensory organ precursor cells that Cyclin A is recruited in prophase by Frizzled/Dishevelled, regulating division orientation.
- Pénélope Darnat
- , Angélique Burg
- & Agnès Audibert
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Article
| Open Access
3D chromatin remodelling in the germ line modulates genome evolutionary plasticity
The role of genome folding in the heritability and evolvability of structural variations is not well understood. Here the authors investigate the impact of the three-dimensional genome topology of germ cells in the formation and transmission of gross structural genomic changes detected from comparing whole-genome sequences of 14 rodent species.
- Lucía Álvarez-González
- , Frances Burden
- & Aurora Ruiz-Herrera
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Article
| Open Access
Stable inheritance of H3.3-containing nucleosomes during mitotic cell divisions
How nucleosome assembly of parental histones is regulated following DNA replication is still an open question. Here the authors show that unlike deposition of new histones H3.1 and H3.3 that utilizes different histone chaperones, parental H3.1 and H3.3 are both stably inherited during mitotic cell division in mouse embryonic stem cells, and this involves histone chaperones Mcm2, Pole3 and Pole4.
- Xiaowei Xu
- , Shoufu Duan
- & Zhiguo Zhang
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| Open Access
Spindle motility skews division site determination during asymmetric cell division in Physcomitrella
In plants, the site of asymmetric cell division (ACD) is generally thought to be determined by the preprophase band and the mitotic spindle is typically static. However, the authors show here that the moss Physcomitrella has motile mitotic spindles that can skew ACD in the absence of preprophase bands.
- Elena Kozgunova
- , Mari W. Yoshida
- & Gohta Goshima
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| Open Access
Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation
Female carriers of BRCA1 mutations possess high breast cancer risk, which may reflect deficient growth control of mammary progenitor cells. Here, the authors study progenitor-enriched fractions from these carriers and describe a loss of PLK1-mediated mitotic spindle positioning and an inability of the progeny to acquire features of mature luminal cells.
- Zhengcheng He
- , Ryan Ghorayeb
- & Christopher A. Maxwell
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Article
| Open Access
Tension can directly suppress Aurora B kinase-triggered release of kinetochore-microtubule attachments
Tension stabilizes properly attached microtubules to kinetochores during chromosome segregation, and lack of tension leads to release. Here the authors show that tension directly suppresses Aurora B kinase mediated destabilization of reconstituted kinetochore-microtubule attachments, likely ensuring accurate chromosome segregation.
- Anna K. de Regt
- , Cordell J. Clark
- & Sue Biggins
The divisome but not the elongasome organizes capsule synthesis in Streptococcus pneumoniae