bims-micesi 2022-12-11 papers

Issue of 2022‒12‒11
four papers selected by
Valentina Piano
Uniklinik Köln

Commun Biol. 2022 Dec 06. 5(1): 1335

The deubiquitinating enzyme complex BRISC regulates Aurora B activation via lysine-63-linked ubiquitination in mitosis.

Qin Li, Yanfang Ma, Fen Chang, Yongjie Xu, Jingcheng Deng, Junyi Duan, Wei Jiang, Qihua He, Luzheng Xu, Lijun Zhong, Genze Shao, Li Li.

Faithful chromosome segregation requires bi-oriented kinetochore-microtubule attachment on the metaphase spindle. Aurora B kinase, the catalytic core of the chromosome passage complex (CPC), plays a crucial role in this process. Aurora B activation has widely been investigated in the context of protein phosphorylation. Here, we report that Aurora B is ubiquitinated in mitosis through lysine-63 ubiquitin chains (K63-Ub), which is required for its activation. Mutation of Aurora B at its primary K63 ubiquitin site inhibits its activation, reduces its kinase activity, and disrupts the association of Aurora B with other components of CPC, leading to severe mitotic defects and cell apoptosis. Moreover, we identify that BRCC36 isopeptidase complex (BRISC) is the K63-specific deubiquitinating enzyme for Aurora B. BRISC deficiency augments the accumulation of Aurora B K63-Ubs, leading to Aurora B hyperactivation and erroneous chromosome-microtubule attachments. These findings define the role of K63-linked ubiquitination in regulating Aurora B activation and provide a potential site for Aurora B-targeting drug design.

DOI: https://doi.org/10.1038/s42003-022-04299-4

Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01636-9. [Epub ahead of print]41(10): 111753

Chromosome arm length, and a species-specific determinant, define chromosome arm width.

Yasutaka Kakui, Christopher Barrington, Yoshiharu Kusano, Rahul Thadani, Todd Fallesen, Toru Hirota, Frank Uhlmann.

Mitotic chromosomes in different organisms adopt various dimensions. What defines these dimensions is scarcely understood. Here, we compare mitotic chromosomes in budding and fission yeasts harboring similarly sized genomes distributed among 16 or 3 chromosomes, respectively. Hi-C analyses and superresolution microscopy reveal that budding yeast chromosomes are characterized by shorter-ranging mitotic chromatin contacts and are thinner compared with the thicker fission yeast chromosomes that contain longer-ranging mitotic contacts. These distinctions persist even after budding yeast chromosomes are fused to form three fission-yeast-length entities, revealing a species-specific organizing principle. Species-specific widths correlate with the known binding site intervals of the chromosomal condensin complex. Unexpectedly, within each species, we find that longer chromosome arms are always thicker and harbor longer-ranging contacts, a trend that we also observe with human chromosomes. Arm length as a chromosome width determinant informs mitotic chromosome formation models.

Keywords: CP: Cell biology; H. sapiens; Hi-C; S. cerevisiae; S. pombe; chromatin interactions; chromosomes; condensin; mitosis; superresolution microscopy

DOI: https://doi.org/10.1016/j.celrep.2022.111753

Med Image Anal. 2022 Nov 23. pii: S1361-8415(22)00331-0. [Epub ahead of print]84 102703

A generalizable and robust deep learning algorithm for mitosis detection in multicenter breast histopathological images.

Xiyue Wang, Jun Zhang, Sen Yang, Jingxi Xiang, Feng Luo, Minghui Wang, Jing Zhang, Wei Yang, Junzhou Huang, Xiao Han.

Mitosis counting of biopsies is an important biomarker for breast cancer patients, which supports disease prognostication and treatment planning. Developing a robust mitotic cell detection model is highly challenging due to its complex growth pattern and high similarities with non-mitotic cells. Most mitosis detection algorithms have poor generalizability across image domains and lack reproducibility and validation in multicenter settings. To overcome these issues, we propose a generalizable and robust mitosis detection algorithm (called FMDet), which is independently tested on multicenter breast histopathological images. To capture more refined morphological features of cells, we convert the object detection task as a semantic segmentation problem. The pixel-level annotations for mitotic nuclei are obtained by taking the intersection of the masks generated from a well-trained nuclear segmentation model and the bounding boxes provided by the MIDOG 2021 challenge. In our segmentation framework, a robust feature extractor is developed to capture the appearance variations of mitotic cells, which is constructed by integrating a channel-wise multi-scale attention mechanism into a fully convolutional network structure. Benefiting from the fact that the changes in the low-level spectrum do not affect the high-level semantic perception, we employ a Fourier-based data augmentation method to reduce domain discrepancies by exchanging the low-frequency spectrum between two domains. Our FMDet algorithm has been tested in the MIDOG 2021 challenge and ranked first place. Further, our algorithm is also externally validated on four independent datasets for mitosis detection, which exhibits state-of-the-art performance in comparison with previously published results. These results demonstrate that our algorithm has the potential to be deployed as an assistant decision support tool in clinical practice. Our code has been released at https://github.com/Xiyue-Wang/1st-in-MICCAI-MIDOG-2021-challenge.

Keywords: Deep learning; Domain shift; Feature extraction; Histopathology; Mitosis detection

DOI: https://doi.org/10.1016/j.media.2022.102703

Sci Rep. 2022 Dec 03. 12(1): 20899

The rate of microtubule breaking increases exponentially with curvature.

Stanislav Tsitkov, Juan B Rodriguez, Neda M Bassir Kazeruni, May Sweet, Takahiro Nitta, Henry Hess.

Microtubules, cylindrical assemblies of tubulin proteins with a 25 nm diameter and micrometer lengths, are a central part of the cytoskeleton and also serve as building blocks for nanobiodevices. Microtubule breaking can result from the activity of severing enzymes and mechanical stress. Breaking can lead to a loss of structural integrity, or an increase in the numbers of microtubules. We observed breaking of taxol-stabilized microtubules in a gliding motility assay where microtubules are propelled by surface-adhered kinesin-1 motor proteins. We find that over 95% of all breaking events are associated with the strong bending following pinning events (where the leading tip of the microtubule becomes stuck). Furthermore, the breaking rate increased exponentially with increasing curvature. These observations are explained by a model accounting for the complex mechanochemistry of a microtubule. The presence of severing enzymes is not required to observe breaking at rates comparable to those measured previously in cells.

DOI: https://doi.org/10.1038/s41598-022-24912-0