bims-micesi 2023-04-09 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2023–04–09
eleven papers selected by
Valentina Piano, Uniklinik Köln

Meiotic cells escape prolonged spindle checkpoint activity through kinetochore silencing and slippage.
Double-checking chromosome segregation.
Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification.
The first mitotic division: a perilous bridge connecting the zygote and the early embryo.
The microtubule cytoskeleton of radial glial progenitor cells.
Structural changes in chromosomes driven by multiple condensin motors during mitosis.
Histone H3 phospho-regulation by KimH3 in both interphase and mitosis.
Multi CNN based automatic detection of mitotic nuclei in breast histopathological images.
Advances in holliday junction recognition protein (HJURP): Structure, molecular functions, and roles in cancer.
Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.
Maternal genetic polymorphisms in the major mitotic checkpoint genes MAD1L1 and MAD2L1 associated with the risk of survival in abnormal chromosomal fetuses.

PLoS Genet. 2023 Apr 05. 19(4): e1010707

Meiotic cells escape prolonged spindle checkpoint activity through kinetochore silencing and slippage.

Anne MacKenzie, Victoria Vicory, Soni Lacefield.

To prevent chromosome mis-segregation, a surveillance mechanism known as the spindle checkpoint delays the cell cycle if kinetochores are not attached to spindle microtubules, allowing the cell additional time to correct improper attachments. During spindle checkpoint activation, checkpoint proteins bind the unattached kinetochore and send a diffusible signal to inhibit the anaphase promoting complex/cyclosome (APC/C). Previous work has shown that mitotic cells with depolymerized microtubules can escape prolonged spindle checkpoint activation in a process called mitotic slippage. During slippage, spindle checkpoint proteins bind unattached kinetochores, but the cells cannot maintain the checkpoint arrest. We asked if meiotic cells had as robust of a spindle checkpoint response as mitotic cells and whether they also undergo slippage after prolonged spindle checkpoint activity. We performed a direct comparison between mitotic and meiotic budding yeast cells that signal the spindle checkpoint through two different assays. We find that the spindle checkpoint delay is shorter in meiosis I or meiosis II compared to mitosis, overcoming a checkpoint arrest approximately 150 minutes earlier in meiosis than in mitosis. In addition, cells in meiosis I escape spindle checkpoint signaling using two mechanisms, silencing the checkpoint at the kinetochore and through slippage. We propose that meiotic cells undertake developmentally-regulated mechanisms to prevent persistent spindle checkpoint activity to ensure the production of gametes.

DOI: https://doi.org/10.1371/journal.pgen.1010707
J Cell Biol. 2023 May 01. pii: e202301106. [Epub ahead of print]222(5):

Double-checking chromosome segregation.

Helder Maiato, Sónia Silva.

Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei-key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore-microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability.

DOI: https://doi.org/10.1083/jcb.202301106
Mol Biol Cell. 2023 Apr 05. mbcE22070296

Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification.

Dayna L Mercadante, William A Aaron, Sarah D Olson, Amity L Manning.

During cell division, the microtubule nucleating and organizing organelle, known as the centrosome, is a critical component of the mitotic spindle. In cells with two centrosomes, each centrosome functions as an anchor point for microtubules, leading to the formation of a bipolar spindle and progression through a bipolar cell division. When extra centrosomes are present, multipolar spindles form and the parent cell may divide into more than two daughter cells. Cells that are born from multipolar divisions are not viable and hence clustering of extra centrosomes and progression to a bipolar division are critical determinants of viability in cells with extra centrosomes. We combine experimental approaches with computational modeling to define a role for cortical dynein in centrosome clustering. We show that centrosome clustering fails and multipolar spindles dominate when cortical dynein distribution or activity is experimentally perturbed. Our simulations further reveal that centrosome clustering is sensitive to the distribution of dynein on the cortex. Together, these results indicate that dynein's cortical localization alone is insufficient for effective centrosome clustering and instead, dynamic relocalization of dynein from one side of the cell to the other throughout mitosis promotes timely clustering and bipolar cell division in cells with extra centrosomes.

DOI: https://doi.org/10.1091/mbc.E22-07-0296
Hum Reprod. 2023 Apr 07. pii: dead067. [Epub ahead of print]

The first mitotic division: a perilous bridge connecting the zygote and the early embryo.

Giovanni Coticchio, Danilo Cimadomo, Greta Chiara Cermisoni, Laura Rienzi, Enrico Papaleo, Filippo Maria Ubaldi, Andrea Borini, Lucia De Santis.

  Human embryos are very frequently affected by maternally inherited aneuploidies, which in the vast majority of cases determine developmental failure at pre- or post-implantation stages. However, recent evidence, generated by the alliance between diverse technologies now routinely employed in the IVF laboratory, has revealed a broader, more complex scenario. Aberrant patterns occurring at the cellular or molecular level can impact at multiple stages of the trajectory of development to blastocyst. In this context, fertilization is an extremely delicate phase, as it marks the transition between gametic and embryonic life. Centrosomes, essential for mitosis, are assembled ex novo from components of both parents. Very large and initially distant nuclei (the pronuclei) are brought together and positioned centrally. The overall cell arrangement is converted from being asymmetric to symmetric. The maternal and paternal chromosome sets, initially separate and scattered within their respective pronuclei, become clustered where the pronuclei juxtapose, to facilitate their assembly in the mitotic spindle. The meiotic spindle is replaced by a segregation machinery that may form as a transient or persistent dual mitotic spindle. Maternal proteins assist the decay of maternal mRNAs to allow the translation of newly synthesized zygotic transcripts. The diversity and complexity of these events, regulated in a precise temporal order and occurring in narrow time windows, make fertilization a highly error-prone process. As a consequence, at the first mitotic division, cellular or genomic integrity may be lost, with fatal consequences for embryonic development.

Keywords:  chromosomes; development; embryo; fertilization; oocyte; pronuclei

DOI:  https://doi.org/10.1093/humrep/dead067
Curr Opin Neurobiol. 2023 Mar 30. pii: S0959-4388(23)00034-X. [Epub ahead of print]80 102709

The microtubule cytoskeleton of radial glial progenitor cells.

Ryszard Wimmer, Alexandre D Baffet.

A high number of genetic mutations associated with cortical malformations are found in genes coding for microtubule-related factors. This has stimulated research to understand how the various microtubule-based processes are regulated to build a functional cerebral cortex. Here, we focus our review on the radial glial progenitor cells, the stem cells of the developing neocortex, summarizing research mostly performed in rodents and humans. We highlight how the centrosomal and acentrosomal microtubule networks are organized during interphase to support polarized transport and proper attachment of the apical and basal processes. We describe the molecular mechanism for interkinetic nuclear migration (INM), a microtubule-dependent oscillation of the nucleus. Finally, we describe how the mitotic spindle is built to ensure proper chromosome segregation, with a strong focus on factors mutated in microcephaly.

DOI: https://doi.org/10.1016/j.conb.2023.102709
Cell Rep. 2023 Apr 06. pii: S2211-1247(23)00359-5. [Epub ahead of print]42(4): 112348

Structural changes in chromosomes driven by multiple condensin motors during mitosis.

Atreya Dey, Guang Shi, Ryota Takaki, D Thirumalai.

  We create a computational framework that utilizes loop extrusion (LE) by multiple condensin I/II motors to predict changes in chromosome organization during mitosis. The theory accurately reproduces the experimental contact probability profiles for the mitotic chromosomes in HeLa and DT40 cells. The LE rate is smaller at the start of mitosis and increases as the cells approach metaphase. Condensin II-mediated mean loop size is about six times larger than loops because of condensin I. The loops, which overlap each other, are stapled to a central dynamically changing helical scaffold formed by the motors during the LE process. A polymer physics-based data-driven method that uses the Hi-C contact map as the only input shows that the helix is characterized as random helix perversions (RHPs) in which the handedness changes randomly along the scaffold. The theoretical predictions, which are testable using imaging experiments, do not contain any parameters.

Keywords:  CP: Molecular biology; HIPPS; Hi-C-polymer-physics structures; loop extrusion; mitotic chromosomes; multiple condensin motors; random helix perversion; scrunching mechanism; symmetric and asymmetric loop extrusion

DOI:  https://doi.org/10.1016/j.celrep.2023.112348
iScience. 2023 Apr 21. 26(4): 106372

Histone H3 phospho-regulation by KimH3 in both interphase and mitosis.

Junjun Wang, Xiaofei Tian, Chuanlin Feng, Chao Song, Biao Yu, Ying Wang, Xinmiao Ji, Xin Zhang.

  Histone H3 is phosphorylated at Ser10 by multiple kinases, and many of them are anti-cancer targets. Here, we report the first kinase that can phosphorylate H3Ser10 in both interphase and mitosis, which we named KimH3 (kinase of interphase and mitotic Histone H3). Meta-analysis indicates that KimH3 is upregulated in a broad spectrum of human cancers and its high expression is correlated with reduced the median survival time of cancer patients. In mitosis, CDK1 phosphorylates KimH3, which then phosphorylates H3Ser10 to regulate cell cycle procession. In interphase, EGF induces KimH3 activation and H3Ser10 phosphorylation, which is involved in MAPK-ERK1/2 signaling pathway to activate immediate-early genes transcription. Consequently, a small molecule inhibitor of KimH3 significantly inhibited tumor growth in mice. This is not only consistent with the dual roles of KimH3 in both interphase and mitotic Histone H3 phosphorylation, but also reveals it as an important potential anti-cancer target.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.106372
Comput Biol Med. 2023 Mar 22. pii: S0010-4825(23)00280-9. [Epub ahead of print]158 106815

Multi CNN based automatic detection of mitotic nuclei in breast histopathological images.

Abdul Rahim Shihabuddin, Sabeena Beevi K.

  In breast cancer diagnosis, the number of mitotic cells in a specific area is an important measure. It indicates how far the tumour has spread, which has consequences for forecasting the aggressiveness of cancer. Mitosis counting is a time-consuming and challenging technique that a pathologist does manually by examining Hematoxylin and Eosin (H&E) stained biopsy slices under a microscope. Due to limited datasets and the resemblance between mitotic and non-mitotic cells, detecting mitosis in H&E stained slices is difficult. By assisting in the screening, identifying, and labelling of mitotic cells, computer-aided mitosis detection technologies make the entire procedure much easier. For computer-aided detection approaches of smaller datasets, pre-trained convolutional neural networks are extensively employed. The usefulness of a multi CNN framework with three pre-trained CNNs is investigated in this research for mitosis detection. Features were collected from histopathology data and identified using VGG16, ResNet50, and DenseNet201 pre-trained networks. The proposed framework utilises all training folders of the MITOS dataset provided for the MITOS-ATYPIA contest 2014 and all the 73 folders of the TUPAC16 dataset. Each pre-trained Convolutional Neural Network model, such as VGG16, ResNet50 and DenseNet201, provides an accuracy of 83.22%, 73.67%, and 81.75%, respectively. Different combinations of these pre-trained CNNs constitute a multi CNN framework. Performance measures of multi CNN consisting of 3 pre-trained CNNs with Linear SVM give 93.81% precision and 92.41% F1-score compared to multi CNN combinations with other classifiers such as Adaboost and Random Forest.

Keywords:  Breast cancer; MITOS-ATYPIA-14; Mitosis; MultiCNN; TUPAC16

DOI:  https://doi.org/10.1016/j.compbiomed.2023.106815
Front Cell Dev Biol. 2023 ;11 1106638

Advances in holliday junction recognition protein (HJURP): Structure, molecular functions, and roles in cancer.

Lin Li, Qiang Yuan, Yue-Ming Chu, Hang-Yu Jiang, Ju-Hua Zhao, Qiang Su, Dan-Qun Huo, Xiao-Fen Zhang.

  Oncogenes are increasingly recognized as important factors in the development and progression of cancer. Holliday Junction Recognition Protein (HJURP) is a highly specialized mitogenic protein that is a chaperone protein of histone H3. The HJURP gene is located on chromosome 2q37.1 and is involved in nucleosome composition in the mitotic region, forming a three-dimensional crystal structure with Centromere Protein A (CENP-A) and the histone 4 complex. HJURP is involved in the recruitment and assembly of centromere and kinetochore and plays a key role in stabilizing the chromosome structure of tumor cells, and its dysfunction may contribute to tumorigenesis. In the available studies HJURP is upregulated in a variety of cancer tissues and cancer cell lines and is involved in tumor proliferation, invasion, metastasis and immune response. In an in vivo model, overexpression of HJURP in most cancer cell lines promotes cell proliferation and invasiveness, reduces susceptibility to apoptosis, and promotes tumor growth. In addition, upregulation of HJURP was associated with poorer prognosis in a variety of cancers. These properties suggest that HJURP may be a possible target for the treatment of certain cancers. Various studies targeting HJURP as a prognostic and therapeutic target for cancer are gradually attracting interest and attention. This paper reviews the functional and molecular mechanisms of HJURP in a variety of tumor types with the aim of providing new targets for future cancer therapy.

Keywords:  CENP-A; HJURP; cancer; centromere; prognosis

DOI:  https://doi.org/10.3389/fcell.2023.1106638
Cell Rep. 2023 Apr 05. pii: S2211-1247(23)00354-6. [Epub ahead of print]42(4): 112343

Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.

Qiaoqiao Zhang, Hui Zheng, Shengye Yang, Tong Feng, Minwen Jie, Haiyang Chen, Hao Jiang.

  Lipophagy, the process of selective catabolism of lipid droplets (LDs) by autophagy, maintains lipid homeostasis and provides cellular energy under metabolic adaptation, yet its underlying mechanism remains largely ambiguous. Here, we show that the Bub1-Bub3 complex, the crucial regulator involved in the whole process of chromosome alignment and separation during mitosis, controls the fasting-induced lipid catabolism in the fat body (FB) of Drosophila. Bidirectional deviations of the Bub1 or Bub3 level affect the consumption of triacylglycerol (TAG) of fat bodies and the survival rate of adult flies under starving. Moreover, Bub1 and Bub3 work together to attenuate lipid degradation via macrolipophagy upon fasting. Thus, we uncover physiological roles of the Bub1-Bub3 complex on metabolic adaptation and lipid metabolism beyond their canonical mitotic functions, providing insights into the in vivo functions and molecular mechanisms of macrolipophagy during nutrient deprivation.

Keywords:  CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.112343
Front Genet. 2023 ;14 1105184

Maternal genetic polymorphisms in the major mitotic checkpoint genes MAD1L1 and MAD2L1 associated with the risk of survival in abnormal chromosomal fetuses.

Ying Chan, Yize Liu, Yamin Kong, Weiming Xu, Xiaohong Zeng, Haichun Li, Yan Guo, Xinhua Tang, Jinman Zhang, Baosheng Zhu.

  Background: The genetic etiology of fetal chromosome abnormalities remains unknown, which brings about an enormous burden for patients, families, and society. The spindle assembly checkpoint (SAC) controls the normal procedure of chromosome disjunction and may take part in the process. Objective: The aim of this study was to explore the association between polymorphisms of MAD1L1 rs1801368 and MAD2L1 rs1283639804, involved in SAC and fetal chromosome abnormalities. Methods: The case-control study collected 563 cases and 813 health controls to test the genotypes of MAD1L1 rs1801368 and MAD2L1 rs1283639804 polymorphisms by polymerase chain reaction-restrictive fragment length polymorphism methods (PCR-RFLP). Results: MAD1L1 rs1801368 polymorphism was associated with fetal chromosome abnormalities alone or combined to lower homocysteine (HCY) levels (alone: dominant: OR: 1.75, 95%CI: 1.19-2.57, and p = 0.005; CT vs. CC: OR = 0.73, 95%CI: 0.57-0.94, and p = 0.016; lower HCY: C vs. T: OR = 0.74, 95%CI: 0.57-0.95, and p = 0.02; dominant: OR = 1.75, 95%CI: 0.79-1.92, and p = 0.005). No significant differences were found in other genetic models or subgroups (p > 0.05, respectively). MAD2L1 rs1283639804 polymorphism revealed a sole genotype in the studied population. HCY is significantly associated with fetal chromosome abnormalities in younger groups (OR: 1.78, 95%CI: 1.28-2.47, and p = 0.001). Conclusion: The results implied that the polymorphism of MAD1L1 rs1801368 may become the susceptibility factor to fetal chromosome abnormalities alone or combined to lower HCY levels but not to MAD2L1 rs1283639804 polymorphism. In addition, HCY significantly affects fetal chromosomal abnormalities in younger women.

Keywords:  MAD1L1; MAD2L1; fetal chromosome abnormality; homocysteine(HYC); polymorphism

DOI:  https://doi.org/10.3389/fgene.2023.1105184