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Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown
Telomeric entanglements arising from stalled telomeric replication forks can cause mitotic catastrophe in dividing cells. Here, the authors show that resolution of such entanglements in fission yeast requires rapid exposure of the DNA to the cytoplasm during anaphase.
- Rishi Kumar Nageshan
- , Raquel Ortega
- & Julia Promisel Cooper
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Article
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Ran-GTP assembles a specialized spindle structure for accurate chromosome segregation in medaka early embryos
Mitotic spindle assembles in each blastomere to segregate duplicated chromosomes during cleavage of the fertilized egg. Here, the authors establish functional assays in fish embryos and find that Ran-GTP assembles a microtubule network at the metaphase spindle center that is essential for chromosome segregation.
- Ai Kiyomitsu
- , Toshiya Nishimura
- & Tomomi Kiyomitsu
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Article
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Mid-cell migration of the chromosomal terminus is coupled to origin segregation in Escherichia coli
In slow-growing Escherichia coli, the chromosomal terminus is initially located at the new pole and must therefore migrate to midcell during replication to reproduce the same pattern in the daughter cells. Here, Sadhir & Murray use high-throughput time-lapse microscopy to quantify this transition, its timing and its relationship to chromosome segregation, identifying an unexplored connection between the origin of replication locus and the terminus.
- Ismath Sadhir
- & Seán M. Murray
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Article
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Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1
Mild replication stress leads to premature centriole disengagement while delaying mitotic onset. Here, Dwivedi et al. demonstrate that this results from sub-critical Plk1 kinase activity, enabling centrosome cycling but impeding rapid mitotic entry.
- Devashish Dwivedi
- , Daniela Harry
- & Patrick Meraldi
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Article
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CENP-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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Article
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DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability
Genomic instability can induce an anti-tumour immune response via activation of the cGAS-STING pathway following the formation of micronuclei (MN). Here, the authors identify a role for DNAJA2 in maintenance of chromosomal segregation. Loss of which increased MN formation and cGAS-STING pathway activation, increasing response to immune checkpoint blockade.
- Yaping Huang
- , Changzheng Lu
- & Guo-Min Li
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Article
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Kinetochore component function in C. elegans oocytes revealed by 4D tracking of holocentric chromosomes
The exact function of kinetochore proteins in meiosis remains unclear. Using live imaging of C. elegans oocytes, the authors systematically study the contribution of each kinetochore sub-complex and describe a push-pull mechanism that confers robustness to chromosome segregation.
- Laras Pitayu-Nugroho
- , Mélanie Aubry
- & Julien Dumont
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Article
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Multiple ParA/MinD ATPases coordinate the positioning of disparate cargos in a bacterial cell
The ParA/MinD family of ATPases organize diverse genetic- and protein-based cellular cargos in bacteria. Here, Pulianmackal et al. find that over a third of sequenced bacterial genomes encode multiple ParA/MinD ATPases, and show how multiple ParA/MinD ATPases coexist and function to position diverse cargos in the same bacterial cell.
- Lisa T. Pulianmackal
- , Jose Miguel I. Limcaoco
- & Anthony G. Vecchiarelli
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Article
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Rio1 downregulates centromeric RNA levels to promote the timely assembly of structurally fit kinetochores
Kinetochores assemble on centromeres via histone H3 variant CENP-A and low levels of centromere transcripts (cenRNAs). Here the authors show the Rio1 kinase limits cenRNA production by reducing RNAPII accessibility and promotes cenRNA degradation by the 5’− 3’exoribonuclease Rat1.
- Ksenia Smurova
- , Michela Damizia
- & Peter De Wulf
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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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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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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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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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Single-molecule analysis of specificity and multivalency in binding of short linear substrate motifs to the APC/C
The authors used novel single-molecule technology to measure the affinity of interactions between the ubiquitin ligase APC/C and its substrates, providing insights into the control of APC/C substrate destruction during mitosis.
- Nairi Hartooni
- , Jongmin Sung
- & David O. Morgan
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Article
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NuMA regulates mitotic spindle assembly, structural dynamics and function via phase separation
Mitotic spindle assembly is required for proper cell division, but many underlying mechanisms remain unclear. Here, the authors show that NuMa undergoes liquid-liquid phase separation, condensing on spindle poles during mitotic entry and enriching critical components to promote spindle assembly.
- Mengjie Sun
- , Mingkang Jia
- & Chuanmao Zhang
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Article
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Counteraction between Astrin-PP1 and Cyclin-B-CDK1 pathways protects chromosome-microtubule attachments independent of biorientation
Chromosome instability frequently occurs due to issues with chromosome-microtubule attachments. Here the authors show that the Astrin-PP1 and Cyclin-B-CDK1 pathways counteract each other to protect chromosome-microtubule attachments independent of biorientation.
- Xinhong Song
- , Duccio Conti
- & Viji M. Draviam
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Article
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A genetically-encoded crosslinker screen identifies SERBP1 as a PKCε substrate influencing translation and cell division
PKCε is known to exert a role in genome protection by directly phosphorylating and switching the specificity of Aurora B. Here the authors identify SERBP1 as a parallel mitotic PKCε substrate controlling translation and ensuring the integrity of chromosome segregation and successful cell division.
- Silvia Martini
- , Khalil Davis
- & Peter J. Parker
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Article
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Spatiotemporal coordination of the RSF1-PLK1-Aurora B cascade establishes mitotic signaling platforms
During cell division, chromosome alignment is engendered by connection of microtubules to kinetochores, coordinated by Aurora B and PLK1. Here, the authors show that the RSF1-PLK1 axis creates an activating phosphorylation on T236 in the GT motif of Aurora B and this is indispensable for Aurora B activation.
- Ho-Soo Lee
- , Sunwoo Min
- & Hyeseong Cho
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Article
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Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing
A possible undesired outcome of CRISPR-Cas9 germline editing is unwanted karyotype alterations. Here the authors track aberrations through three divisions of embryonic development following Cas9 editing.
- Stamatis Papathanasiou
- , Styliani Markoulaki
- & David Pellman
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Article
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The RAD51 recombinase protects mitotic chromatin in human cells
RAD51 is a well known player of DNA repair and homologous recombination. Here the authors reveal a function for RAD51 in protecting under-replicated DNA in mitotic human cells, promoting mitotic DNA synthesis (MiDAS) and successful chromosome segregation.
- Isabel E. Wassing
- , Emily Graham
- & Fumiko Esashi
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Article
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The structure of the bacterial DNA segregation ATPase filament reveals the conformational plasticity of ParA upon DNA binding
ParA is an ATPase involved in the segregation of newly replicated DNA in bacteria. Here, structures of a ParA filament bound to DNA and of ParA in various nucleotide states offer insight into its conformational changes upon DNA binding and filament assembly, including the basis for ParA’s cooperative binding to DNA.
- Alexandra V. Parker
- , Daniel Mann
- & Julien R. C. Bergeron
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Article
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Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome
Patients with Cornelia de Lange Syndrome (CdLS) often have mutations in cohesin and its regulators; however, the molecular mechanism driving CdLS phenotypes is not well established. Here the authors reveal system skeletal organization genes are downregulated and show that cohesin and its loader Nipbl have altered and decreased genome-wide localization.
- Patricia Garcia
- , Rita Fernandez-Hernandez
- & Ethel Queralt
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Perspective
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Towards a synthetic cell cycle
A key feature of living cells is the cell cycle. In this Perspective, the authors explore attempts to recreate this process and what is still required for an integrated synthetic cell cycle.
- Lorenzo Olivi
- , Mareike Berger
- & John van der Oost
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Article
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A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes
Securin inhibits the protease separase and must be removed before anaphase to ensure timely chromosome segregation. Here, the authors define a mechanism of securin destruction in prometaphase I in mouse oocytes and demonstrate its importance for successful meiotic progression.
- Christopher Thomas
- , Benjamin Wetherall
- & Suzanne Madgwick
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Comment
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Ploidy dynamics increase the risk of liver cancer initiation
Liver cancer typically arises after years of inflammatory insults to hepatocytes. These cells can change their ploidy state during health and disease. Whilst polyploidy may offer some protection, new research shows it may also promote the formation of liver tumours.
- Miryam Müller
- , Stephanie May
- & Thomas G. Bird
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Article
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Bridgin connects the outer kinetochore to centromeric chromatin
The kinetochore is a multi-complex structure that helps attach chromosomes to spindle microtubules, ensuring accurate chromosome segregation during cell division. Kinetochores are thought to be evolutionarily conserved, but which components are conserved is unclear. Here, the authors report that some members of the fungal phylum of Basidomycota lack many conventional kinetochore linker proteins. Instead, they possess a human Ki67-like protein that bridges the outer part of the kinetochore to centromere DNA, which may compensate for the loss of a conventional linker.
- Shreyas Sridhar
- , Tetsuya Hori
- & Kaustuv Sanyal
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Article
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Developmental potential of aneuploid human embryos cultured beyond implantation
Aneuploidy, abnormal chromosome number, is a major cause of early pregnancy loss. Here the authors determine the extent of post-implantation development of human embryos with common aneuploidies in culture, finding developmental arrest of monosomy 21 embryos, and trophoblast hypo-proliferation in trisomy 16 embryos.
- Marta N. Shahbazi
- , Tianren Wang
- & Magdalena Zernicka-Goetz
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Article
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Post-replicative pairing of sister ter regions in Escherichia coli involves multiple activities of MatP
Protein, MatP, binds to and delays segregation of the ter region of the bacterial chromosome before cell division. Here, the authors show that MatP displays multiple activities to promote optimal pairing of sister ter regions until cell division.
- Estelle Crozat
- , Catherine Tardin
- & François Cornet
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Article
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Direct observation of independently moving replisomes in Escherichia coli
How chromosome replication and segregation is organised in E. coli is a matter of debate. Here the authors visualise the bacterial chromosome and the replisomes during DNA replication, providing support for a previously suggested train track model.
- Aleksandre Japaridze
- , Christos Gogou
- & Cees Dekker
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Article
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Prc1-rich kinetochores are required for error-free acentrosomal spindle bipolarization during meiosis I in mouse oocytes
Oocyte meiosis must achieve spindle bipolarization without predefined spatial cues. Yoshida et al. demonstrate that spindle bipolarization during meiosis I in mouse oocytes requires kinetochores to prevent chromosome segregation errors, a phenomenon that does not occur in error-prone human oocytes.
- Shuhei Yoshida
- , Sui Nishiyama
- & Tomoya S. Kitajima
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Article
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Budding yeast complete DNA synthesis after chromosome segregation begins
In the S phase of the cell cycle, the full genome needs to be replicated before cell division occurs. Here, authors show that in budding yeast DNA synthesis is completed after chromosome segregation begins.
- Tsvetomira Ivanova
- , Michael Maier
- & Manuel Mendoza
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Article
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Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1
The BRCA2 tumour suppressor protein is known to play an important role in homologous recombination. Here the authors reveal how the phosphorylation of BRCA2 by Polo-like kinase 1 (PLK1) contributes to the regulation of mitosis.
- Åsa Ehlén
- , Charlotte Martin
- & Aura Carreira
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Article
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Artificially decreasing cortical tension generates aneuploidy in mouse oocytes
The developmental potential of human and murine oocytes is predicted by their mechanical properties. Here the authors show that artificial reduction of cortex tension produces aneuploid mouse oocytes and speculate that this may contribute to the high aneuploidy rate typical of female meiosis.
- Isma Bennabi
- , Flora Crozet
- & Marie-Emilie Terret
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Article
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Degree and site of chromosomal instability define its oncogenic potential
Aneuploidy caused by chromosomal instability is frequently observed in cancer, but little is known about its contribution to tumor development. Here, the authors show that in the mouse intestine, the consequences of aneuploidy are exquisitely dependent on both its extent and anatomical location.
- Wilma H. M. Hoevenaar
- , Aniek Janssen
- & Nannette Jelluma
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Article
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Chromosome organization by a conserved condensin-ParB system in the actinobacterium Corynebacterium glutamicum
The regulation of higher-order chromosome folding and segregation in bacteria is poorly understood. Here, Böhm et al. provide insights into the roles of DNA partitioning protein ParB and SMC condensin complexes in Corynebacterium glutamicum.
- Kati Böhm
- , Giacomo Giacomelli
- & Marc Bramkamp
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Article
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CEP44 ensures the formation of bona fide centriole wall, a requirement for the centriole-to-centrosome conversion
During cell division, centrosomes duplicate and newly formed centrioles must undergo centriole-to-centrosome conversion, but the molecular details are unclear. Here, the authors report that the centriole microtubule-triplet 9-fold structure scaffolds pericentriolar proteins and permits the conversion of centrioles to fully functional centrosomes.
- Enrico S. Atorino
- , Shoji Hata
- & Elmar Schiebel
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Article
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Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation
Lysosomes are intracellular organelles containing degradative enzymes, and leakage of lysosomal contents into the cell is thought to trigger cell death. Here, the authors report that leaky lysosomes may facilitate chromosome separation during cell division.
- Saara Hämälistö
- , Jonathan Lucien Stahl
- & Marja Jäättelä
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Article
| Open Access
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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Article
| Open Access
Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site
Prior to anaphase, securin binds separase and thereby prevents cohesin cleavage. Here, the authors develop a method to produce active securin-free separase, identify a docking motif in cohesin that promotes cleavage, and show that securin interferes with this interaction.
- Laura E. Rosen
- , Joseph E. Klebba
- & David O. Morgan
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Article
| Open Access
Tetraploidy causes chromosomal instability in acentriolar mouse embryos
During cell division, tetraploidy can drive chromosomal instability (CIN) via supernumerary centrosomes, but it is unclear if this is the only route to CIN. Here the authors show that, in early mouse embryos, tetraploidy can drive chromosomal instability by altering microtubule dynamics and attachment.
- Lia Mara Gomes Paim
- & Greg FitzHarris
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Article
| Open Access
Mild replication stress causes chromosome mis-segregation via premature centriole disengagement
Chromosome instability can be caused by replication stress, although the mechanism is unclear. Here, the authors show that inducing mild replication stress in cancerous and non-cancerous cell lines leads to centriole disengagement and the subsequent formation of lagging chromosomes and micronuclei.
- Therese Wilhelm
- , Anna-Maria Olziersky
- & Patrick Meraldi
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Article
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PLK1 facilitates chromosome biorientation by suppressing centromere disintegration driven by BLM-mediated unwinding and spindle pulling
The kinase PLK1 has important roles during cell division, including mitotic entry and bipolar spindle formation. Here, the authors show that PLK1 also functions in centromere protection, with loss leading to DNA unwinding by Bloom’s syndrome helicase and subsequent collapse of chromosome alignment.
- Owen Addis Jones
- , Ankana Tiwari
- & Kok-Lung Chan
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Article
| Open Access
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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Article
| Open Access
Mad1 destabilizes p53 by preventing PML from sequestering MDM2
Mad1 is well characterised for its function in mitosis. Here, the authors describe an interphase role for Mad1 in tumour promotion in which it destabilises p53 by localizing to PML nuclear bodies and displacing MDM2 from the PML-MDM2 complex.
- Jun Wan
- , Samuel Block
- & Beth A. Weaver
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Article
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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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Article
| Open Access
The binding of Borealin to microtubules underlies a tension independent kinetochore-microtubule error correction pathway
How the chromosome passenger complex (CPC) phosphorylates the kinetochores that can be a micron away to control mitotic events is unknown. Here the authors find that the CPC directly binds microtubules near inner centromeres, which controls its ability to phosphorylate kinetochores independently of tension generated by kinetochore microtubule attachments.
- Prasad Trivedi
- , Anatoly V. Zaytsev
- & P. Todd Stukenberg
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Article
| Open Access
Phosphorylation of CENP-A on serine 7 does not control centromere function
Phosphorylation of CENP-A on serine 7 has been proposed to control centromere assembly and function. Here, the authors use gene targeting at both endogenous CENP-A alleles and gene replacement in human cells to demonstrate that CENP-A that cannot be phosphorylated at serine 7 maintains correct CENP-C recruitment, faithful chromosome segregation and long-term cell viability.
- Viviana Barra
- , Glennis A. Logsdon
- & Daniele Fachinetti
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Article
| 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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Review Article
| Open Access
The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA
Centromeres are the chromosomal domains that regulate assembly of the components required for chromosome separation. Here the authors review how centromeres are a potential source of genome instability and link centromere aberrations and rearrangements to human diseases such as cancer.
- V. Barra
- & D. Fachinetti
Sororin is an evolutionary conserved antagonist of WAPL