bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2023–06–18
thirteen papers selected by
Valentina Piano, Uniklinik Köln
  1. Centromere/kinetochore is assembled through CENP-C oligomerization.
  2. Spatial organization and dynamics of chromosomes and microtubules during barley mitosis.
  3. Mitotic tethering enables inheritance of shattered micronuclear chromosomes.
  4. V-Src delocalizes Aurora B by suppressing Aurora B kinase activity during monopolar cytokinesis.
  5. A mitotic glue for shattered chromosomes.
  6. Proline-rich acidic protein 1 upregulates mitotic arrest deficient 1 to promote cisplatin-resistance of colorectal carcinoma by restraining mitotic checkpoint complex assembly.
  7. Putting scaling laws on a physical foundation.
  8. Anillin and the microtubule bundler PRC1 maintain myosin in the contractile ring to ensure completion of cytokinesis.
  9. The Caenorhabditis elegans Shugoshin regulates TAC-1 in cilia.
  10. The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway.
  11. Mitotic inheritance of genetic and epigenetic information via the histone H3.1 variant.
  12. BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation.
  13. Dynamic Metal-Ligand Coordination Boosts CO2 Electroreduction.
  1. Mol Cell. 2023 Jun 06. pii: S1097-2765(23)00379-9. [Epub ahead of print]
    Centromere/kinetochore is assembled through CENP-C oligomerization.
    Masatoshi Hara, Mariko Ariyoshi, Tomoki Sano, Ryu-Suke Nozawa, Soya Shinkai, Shuichi Onami, Isabelle Jansen, Toru Hirota, Tatsuo Fukagawa.
      Kinetochore is an essential protein complex required for accurate chromosome segregation. The constitutive centromere-associated network (CCAN), a subcomplex of the kinetochore, associates with centromeric chromatin and provides a platform for the kinetochore assembly. The CCAN protein CENP-C is thought to be a central hub for the centromere/kinetochore organization. However, the role of CENP-C in CCAN assembly needs to be elucidated. Here, we demonstrate that both the CCAN-binding domain and the C-terminal region that includes the Cupin domain of CENP-C are necessary and sufficient for chicken CENP-C function. Structural and biochemical analyses reveal self-oligomerization of the Cupin domains of chicken and human CENP-C. We find that the CENP-C Cupin domain oligomerization is vital for CENP-C function, centromeric localization of CCAN, and centromeric chromatin organization. These results suggest that CENP-C facilitates the centromere/kinetochore assembly through its oligomerization.
    Keywords:  CCAN; CENP-C; centromere; chromosome segregation; kinetochore assembly; oligomerization
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.023
  2. Plant J. 2023 Jun 16.
    Spatial organization and dynamics of chromosomes and microtubules during barley mitosis.
    Kateřina Kaduchová, Cintia Marchetti, Miroslav Ovečka, Petr Galuszka, Véronique Bergougnoux, Jozef Šamaj, Ales Pecinka.
      Mitosis and cytokinesis are fundamental processes through which somatic cells increase their numbers and allow plant growth and development. Here, we analyzed the organization and dynamics of mitotic chromosomes, nucleoli, and microtubules in living cells of barley root primary meristems using a series of newly developed stable fluorescent protein translational-fusion lines and time-lapse confocal microscopy. The median duration of mitosis from prophase until the end of telophase was 65.2 and 78.2 minutes until the end of cytokinesis. We showed that barley chromosomes frequently start condensation before mitotic preprophase as defined by the organization of microtubules, and maintain it even after entering into the new interphase. Furthermore, we found that the process of chromosome condensation does not finish at metaphase, but gradually continues until the end of mitosis. In summary, our study features resources for in vivo analysis of barley nuclei and chromosomes, and their dynamics during mitotic cell cycle.
    Keywords:  3D nuclear organization; Hordeum vulgare; barley; chromatin; chromosomes; confocal microscopy; crops; live imaging; microtubules; mitosis
    DOI:  https://doi.org/10.1111/tpj.16355
  3. Nature. 2023 Jun 14.
    Mitotic tethering enables inheritance of shattered micronuclear chromosomes.
    Prasad Trivedi, Christopher D Steele, Franco K C Au, Ludmil B Alexandrov, Don W Cleveland.
      Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s)1, is an ubiquitous2 mutational process generating localized and complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by mis-segregation errors in mitosis3,4 or DNA metabolism5-7 that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or following mitotic entry6,8-10. Here we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of mediator of DNA damage checkpoint 1 (MDC1), DNA topoisomerase II-binding protein 1 (TOPBP1) and cellular inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome mis-segregation and shattering after transient inactivation of the spindle assembly checkpoint. Transient, degron-induced reduction in CIP2A following chromosome micronucleation-dependent chromosome shattering is shown to drive acquisition of segmental deletions and inversions. Analyses of pancancer tumour genomes showed that expression of CIP2A and TOPBP1 was increased overall in cancers with genomic rearrangements, including copy number-neutral chromothripsis with minimal deletions, but comparatively reduced in cancers with canonical chromothripsis in which deletions were frequent. Thus, chromatin-bound tethers maintain the proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers.
    DOI:  https://doi.org/10.1038/s41586-023-06216-z
  4. Cell Signal. 2023 Jun 12. pii: S0898-6568(23)00178-X. [Epub ahead of print] 110764
    V-Src delocalizes Aurora B by suppressing Aurora B kinase activity during monopolar cytokinesis.
    Ryoko Ota, Takumi Watanabe, Yuuki Wazawa, Hiroki Kuwajima, Takuya Honda, Shuhei Soeda, Youhei Saito, Ryuzaburo Yuki, Yasunori Fukumoto, Noritaka Yamaguchi, Naoto Yamaguchi, Yuji Nakayama.
      c-Src tyrosine kinase plays roles in a wide range of signaling events and its increased activity is frequently observed in a variety of epithelial and non-epithelial cancers. v-Src, an oncogene first identified in the Rous sarcoma virus, is an oncogenic version of c-Src and has constitutively active tyrosine kinase activity. We previously showed that v-Src induces Aurora B delocalization, resulting in cytokinesis failure and binucleated cell formation. In the present study, we explored the mechanism underlying v-Src-induced Aurora B delocalization. Treatment with the Eg5 inhibitor (+)-S-trityl-L-cysteine (STLC) arrested cells in a prometaphase-like state with a monopolar spindle; upon further inhibition of cyclin-dependent kinase (CDK1) by RO-3306, cells underwent monopolar cytokinesis with bleb-like protrusions. Aurora B was localized to the protruding furrow region or the polarized plasma membrane 30 min after RO-3306 addition, whereas inducible v-Src expression caused Aurora B delocalization in cells undergoing monopolar cytokinesis. Delocalization was similarly observed in monopolar cytokinesis induced by inhibiting Mps1, instead of CDK1, in the STLC-arrested mitotic cells. Importantly, western blotting analysis and in vitro kinase assay revealed that v-Src decreased the levels of Aurora B autophosphorylation and its kinase activity. Furthermore, like v-Src, treatment with the Aurora B inhibitor ZM447439 also caused Aurora B delocalization at concentrations that partially inhibited Aurora B autophosphorylation. Given that phosphorylation of Aurora B by v-Src was not observed, these results suggest that v-Src causes Aurora B delocalization by indirectly suppressing Aurora B kinase activity.
    Keywords:  AZ3146; Aurora B; CDK1; Cytokinesis; Monopolar cytokinesis; Mps1; RO-3306; STLC; V-Src
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110764
  5. Nature. 2023 Jun 14.
    A mitotic glue for shattered chromosomes.
    Yibo Xue, Daniel Durocher.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-01890-5
  6. J Cancer. 2023 ;14(9): 1515-1530
    Proline-rich acidic protein 1 upregulates mitotic arrest deficient 1 to promote cisplatin-resistance of colorectal carcinoma by restraining mitotic checkpoint complex assembly.
    Jintian Song, Yigui Chen, Hui Yu, Liang Zheng, Yi Wang, Dan Li.
      Background: The mechanism underlying cisplatin resistance in colorectal carcinoma (CRC) has not yet been elucidated. This study is aimed to illustrate the indispensable role of proline-rich acidic protein 1 (PRAP1) in cisplatin-resistant CRC. Methods: Cell viability and apoptosis were monitored using cell counting kit-8 and flow cytometry. Immunofluorescence and morphological analysis were used to determine mitotic arrest in cells. In vivo drug resistance was evaluated using a tumor xenograft assay. Results: PRAP1 was highly expressed in cisplatin-resistant CRC. PRAP1-upregulation in HCT-116 cells increased chemoresistance to cisplatin, whereas RNAi-mediated knockdown of PRAP1 sensitized cisplatin-resistant HCT-116 cells (HCT-116/DDP) to cisplatin. PRAP1-upregulation in HCT-116 cells hindered mitotic arrest and the formation of mitotic checkpoint complexes (MCC), followed by an increase in multidrug-resistant proteins such as p-glycoprotein 1 and multidrug resistance-associated protein 1, while PRAP1-knockdown in HCT-116/DDP cells partly restored colcemid-induced mitotic arrest and MCC assembly, resulting in decreased multidrug-resistant protein levels. PRAP1 downregulation-mediated sensitization to cisplatin in HCT-116/DDP cells was abolished by the inhibition of mitotic kinase activity by limiting MCC assembly. Additionally, PRAP1-upregulation increased cisplatin-resistance in CRC in vivo. Mechanistically, PRAP1 increased the expression of mitotic arrest deficient 1 (MAD1), that competitively binds to mitotic arrest deficient 2 (MAD2) in cisplatin-resistant CRC cells, leading to failed assembly of MCC and subsequent chemotherapy resistance. Conclusion: PRAP1-overexpression caused cisplatin resistance in CRC. Possibly, PRAP1 induced an increase in MAD1, which competitively interacted with MAD2 and subsequently restrained the formation of MCC, resulting in CRC cells escape from the supervision of MCC and chemotherapy resistance.
    Keywords:  Proline-rich acidic protein 1; cisplatin resistance; colorectal carcinoma; mitotic arrest deficient 1; spindle assembly checkpoint
    DOI:  https://doi.org/10.7150/jca.84048
  7. Elife. 2023 06 14. pii: e89415. [Epub ahead of print]12
    Putting scaling laws on a physical foundation.
    Yiyang Ye, Jie Lin.
      As a cell changes size during the cell cycle, why does its density remain constant?
    Keywords:  cell biology; cell density regulation; cell volume; mitotic swelling; none; nucleus volume; physics of living systems; pump leak model; scaling laws
    DOI:  https://doi.org/10.7554/eLife.89415
  8. Development. 2023 Jun 15. pii: dev201637. [Epub ahead of print]150(12):
    Anillin and the microtubule bundler PRC1 maintain myosin in the contractile ring to ensure completion of cytokinesis.
    Inês C Santos, Ana M Silva, Reto Gassmann, Ana X Carvalho.
      Cytokinesis is the last step of cell division, when one cell physically divides into two cells. Cytokinesis is driven by an equatorial contractile ring and signals from antiparallel microtubule bundles (the central spindle) that form between the two masses of segregating chromosomes. Bundling of central spindle microtubules is essential for cytokinesis in cultured cells. Using a temperature-sensitive mutant of SPD-1, the homolog of the microtubule bundler PRC1, we demonstrate that SPD-1 is required for robust cytokinesis in the Caenorhabditis elegans early embryo. SPD-1 inhibition results in broadening of the contractile ring, creating an elongated intercellular bridge between sister cells at the last stages of ring constriction that fails to seal. Moreover, depleting anillin/ANI-1 in SPD-1-inhibited cells results in myosin loss from the contractile ring during the second half of furrow ingression, which in turn results in furrow regression and cytokinesis failure. Our results thus reveal a mechanism involving the joint action of anillin and PRC1, which operates during the later stages of furrow ingression to ensure continued functioning of the contractile ring until cytokinesis is complete.
    Keywords:   Caenorhabditis elegans ; Anillin; Cytokinesis; Midzone microtubule bundling; Myosin; PRC1/SPD-1
    DOI:  https://doi.org/10.1242/dev.201637
  9. Sci Rep. 2023 Jun 09. 13(1): 9410
    The Caenorhabditis elegans Shugoshin regulates TAC-1 in cilia.
    R Reed, K Park, B Waddell, T A Timbers, C Li, K Baxi, R M Giacomin, M R Leroux, C E Carvalho.
      The conserved Shugoshin (SGO) protein family is essential for mediating proper chromosome segregation from yeast to humans but has also been implicated in diverse roles outside of the nucleus. SGO's roles include inhibiting incorrect spindle attachment in the kinetochore, regulating the spindle assembly checkpoint (SAC), and ensuring centriole cohesion in the centrosome, all functions that involve different microtubule scaffolding structures in the cell. In Caenorhabditis elegans, a species with holocentric chromosomes, SGO-1 is not required for cohesin protection or spindle attachment but appears important for licensing meiotic recombination. Here we provide the first functional evidence that in C. elegans, Shugoshin functions in another extranuclear, microtubule-based structure, the primary cilium. We identify the centrosomal and microtubule-regulating transforming acidic coiled-coil protein, TACC/TAC-1, which also localizes to the basal body, as an SGO-1 binding protein. Genetic analyses indicate that TAC-1 activity must be maintained below a threshold at the ciliary base for correct cilia function, and that SGO-1 likely participates in constraining TAC-1 to the basal body by influencing the function of the transition zone 'ciliary gate'. This research expands our understanding of cellular functions of Shugoshin proteins and contributes to the growing examples of overlap between kinetochore, centrosome and cilia proteomes.
    DOI:  https://doi.org/10.1038/s41598-023-36430-8
  10. Oncol Res. 2023 ;31(3): 375-388
    The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway.
    Shuizhong Cen, Xiaojie Peng, Jianwen Deng, Haiyun Jin, Zhinan Deng, Xiaohua Lin, D I Zhu, Ming Jin, Yanwen Zhu, Pusheng Zhang, Yunfeng Luo, Hongyan Huang.
      Triple-negative breast cancer (TNBC) is characterized by fast growth, high metastasis, high invasion, and a lack of therapeutic targets. Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression. It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors, but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown. In this study, we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1 (PLK1) activation and participating in mitosis of TNBC cells. We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization (ISH), northern blot, fluorescent in situ hybridization (FISH) and cell nucleus/cytoplasm RNA fraction isolation. High AFAP1-AS1 expression was negatively correlated with overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS) and recurrence-free survival (RFS) in TNBC patients. We explored the function of AFAP1-AS1 by transwell, apoptosis, immunofluorescence (IF) and patient-derived xenograft (PDX) models in vitro and in vivo. We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth, migration and invasion. Mechanistically, AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein. Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression, such as CDC25C, CDK1, BUB1 and TTK. More importantly, AFAP1-AS1 increased lung metastases in a mouse metastasis model. Taken together, AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway. AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.
    Keywords:  AFAP1-AS1; Metastasis; Mitotic catastrophe; PLK1; TNBC
    DOI:  https://doi.org/10.32604/or.2023.028256
  11. Curr Opin Plant Biol. 2023 Jun 09. pii: S1369-5266(23)00066-3. [Epub ahead of print]75 102401
    Mitotic inheritance of genetic and epigenetic information via the histone H3.1 variant.
    Valentin Joly, Yannick Jacob.
      The replication-dependent histone H3.1 variant, ubiquitous in multicellular eukaryotes, has been proposed to play key roles during chromatin replication due to its unique expression pattern restricted to the S phase of the cell cycle. Here, we describe recent discoveries in plants regarding molecular mechanisms and cellular pathways involving H3.1 that contribute to the maintenance of genomic and epigenomic information. First, we highlight new advances concerning the contribution of the histone chaperone CAF-1 and the TSK-H3.1 DNA repair pathway in preventing genomic instability during replication. We then summarize the evidence connecting H3.1 to specific roles required for the mitotic inheritance of epigenetic states. Finally, we discuss the recent identification of a specific interaction between H3.1 and DNA polymerase epsilon and its functional implications.
    Keywords:  Arabidopsis; Chromatin; DNA replication; Epigenetics; Histone modifications; Histone variants
    DOI:  https://doi.org/10.1016/j.pbi.2023.102401
  12. EMBO J. 2023 Jun 12. e113565
    BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation.
    Samuel R Witus, Lisa M Tuttle, Wenjing Li, Alex Zelter, Meiling Wang, Klaiten E Kermoade, Damien B Wilburn, Trisha N Davis, Peter S Brzovic, Weixing Zhao, Rachel E Klevit.
      BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.
    Keywords:  BRCA1/BARD1; DNA repair; chromatin; intrinsically disordered region; ubiquitin
    DOI:  https://doi.org/10.15252/embj.2023113565
  13. J Am Chem Soc. 2023 Jun 13.
    Dynamic Metal-Ligand Coordination Boosts CO2 Electroreduction.
    Xiangdong Kong, Jiankang Zhao, Zifan Xu, Zhengya Wang, Yingying Wu, Yaohui Shi, Hongliang Li, Chuanxu Ma, Jie Zeng, Zhigang Geng.
      The interfacial structure of heterogeneous catalysts determines the reaction rate by adjusting the adsorption behavior of reaction intermediates. Unfortunately, the catalytic performance of conventionally static active sites has always been limited by the adsorbate linear scaling relationship. Herein, we develop a triazole-modified Ag crystal (Ag crystal-triazole) with dynamic and reversible interfacial structures to break such a relationship for boosting the catalytic activity of CO2 electroreduction into CO. On the basis of surface science measurements and theoretical calculations, we demonstrated the dynamic transformation between adsorbed triazole and adsorbed triazolyl on the Ag(111) facet induced by metal-ligand conjugation. During CO2 electroreduction, Ag crystal-triazole with the dynamically reversible transformation of ligands exhibited a faradic efficiency for CO of 98% with a partial current density for CO as high as -802.5 mA cm-2. The dynamic metal-ligand coordination not only reduced the activation barriers of CO2 protonation but also switched the rate-determining step from CO2 protonation to the breakage of C-OH in the adsorbed COOH intermediate. This work provided an atomic-level insight into the interfacial engineering of the heterogeneous catalysts toward highly efficient CO2 electroreduction.
    DOI:  https://doi.org/10.1021/jacs.3c04143
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