Article
Biochemistry & Molecular Biology
Babhrubahan Roy, Janice Sim, Simon J. Y. Han, Ajit P. Joglekar
Summary: The study investigates the interaction between Spc105 and Kre28 in budding yeast KTs. The results show that Spc105 and Kre28 localize at the KT with a 1:1 stoichiometry, and their interaction is important for Spc105 turnover and mutual recruitment at the KTs.
Article
Biochemistry & Molecular Biology
Tobias Raisch, Giuseppe Ciossani, Ennio D'Amico, Verena Cmentowski, Sara Carmignani, Stefano Maffini, Felipe Merino, Sabine Wohlgemuth, Ingrid R. Vetter, Stefan Raunser, Andrea Musacchio
Summary: A high-resolution cryo-EM structure of the ROD-Zwilch-ZW10 complex reveals essential features, such as a farnesyl-binding site required for Spindly binding. In vitro assays demonstrate that the SAC kinase MPS1 is necessary and sufficient for corona assembly at supercritical concentrations of the RZZ-Spindly complex, and the molecular mechanism of phosphorylation-dependent filament nucleation is described.
Review
Cell Biology
Angela R. R. Bunning, Mohan L. L. Gupta Jr.
Summary: Accurate chromosome segregation is essential for cell and organismal viability. The mitotic spindle, composed mainly of dynamic microtubules, plays a crucial role in this process by forming a bipolar configuration and generating tension across sister kinetochores. Recent advances have shed light on the role of tension as a biophysical signal that ensures accurate chromosome segregation by destabilizing aberrant kinetochore-microtubule attachments and reinforcing correct connections.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Soumitra Polley, Helen Mueschenborn, Melina Terbeck, Anna De Antoni, Ingrid R. Vetter, Marileen Dogterom, Andrea Musacchio, Vladimir A. Volkov, Pim J. Huis In 't Veld
Summary: During cell division, the Ndc80 complex plays a crucial role in linking chromosomes to spindle microtubules. This study demonstrates that the Ndc80 loop promotes direct interactions between adjacent Ndc80 complexes, which are necessary for stable end-on kinetochore-microtubule attachment and spindle assembly checkpoint satisfaction. Mutations in the loop impair these interactions and lead to cell arrest in mitosis.
Article
Cell Biology
Wonkyung Oh, Ting Ting Wu, Seo-Yeon Jeong, Ho Jin You, Jung-Hee Lee
Summary: CtIP plays a critical role in regulating mitosis by interacting with TPX2 to control spindle dynamics and regulate the concentration of Aurora A and microtubule intensity at the spindle poles. Depletion of CtIP may lead to improper execution of mitosis and result in chromosomal instability.
Article
Biochemistry & Molecular Biology
Wei Yue, Yue Wang, Tie-Gang Meng, Hong-Yong Zhang, Xin-Ran Zhang, Ying-Chun Ouyang, Yi Hou, Heide Schatten, Zhen-Bo Wang, Qing-Yuan Sun
Summary: This study investigates the role of outer kinetochore protein KNL1 in mouse oocytes and reveals its critical function in ensuring timely and accurate chromosome segregation during oocyte meiotic maturation.
Article
Biochemistry & Molecular Biology
Kazuhiko S. K. Uchida, Minji Jo, Kota Nagasaka, Motoko Takahashi, Norihisa Shindo, Katsushi Shibata, Kozo Tanaka, Hiroshi Masumoto, Tatsuo Fukagawa, Toru Hirota
Summary: The spindle-assembly checkpoint delays anaphase onset in response to microtubule vacancy at kinetochores. Kinetochore stretching is found to be essential for checkpoint silencing by promoting PP1 phosphatase recruitment. Lower frequency of kinetochore stretching is associated with prolonged metaphase in cancer cell lines with chromosomal instability.
Article
Cell Biology
Yanze Jian, Lingyun Nie, Sikai Liu, Yueyue Jiang, Zhen Dou, Xing Liu, Xuebiao Yao, Chuanhai Fu
Summary: The outer kinetochore acts as a platform for SAC initiation and mediating kinetochore-microtubule attachments. The inner kinetochore subcomplex CENP-S-CENP-X's involvement in regulating the SAC and kinetochore-microtubule attachments is not well characterized.
JOURNAL OF CELL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Aurelien Courtois, Shuhei Yoshida, Osamu Takenouchi, Kohei Asai, Tomoya S. Kitajima
Summary: This study demonstrates the importance of stable kinetochore-microtubule attachments in confining MTOC positions at spindle poles and limiting spindle elongation in acentriolar spindles. The gradual MTOC sorting process in the metaphase spindle is crucial for maintaining spindle integrity. Disruption of stable kinetochore-microtubule attachments leads to failure in MTOC confinement and spindle elongation termination.
Article
Biology
William Conway, Robert Kiewisz, Gunar Fabig, Colm P. Kelleher, Hai-Yin Wu, Maya Anjur-Dietrich, Thomas Mueller-Reichert, Daniel J. Needleman
Summary: During eukaryotic cell division, the distribution of kinetochore microtubules (KMTs) in the mitotic spindle is crucial for accurate chromosome segregation. This study investigates the processes that give rise to the observed distribution of KMTs in human cells. The results suggest that KMTs grow away from kinetochores along defined trajectories, with longer KMTs growing more slowly than shorter ones, leading to a mathematical model of kinetochore-fiber self-organization in human mitotic spindles.
Article
Developmental Biology
Marianne Roca, Lydia Besnardeau, Elisabeth Christians, Alex McDougall, Janet Chenevert, Stefania Castagnetti
Summary: The spindle assembly checkpoint (SAC) is responsible for delaying anaphase onset until all chromosomes are correctly attached to spindle microtubules, maintaining genome integrity. In chordate embryos, SAC is inactive or cell-cycle target machinery is unresponsive during early development, allowing mitotic progression despite spindle defects. However, in Phallusia mammillata embryos, the SAC delays mitotic progression from the 8th cleavage divisions and unattached kinetochores are recognized by the SAC machinery after the 7th cell cycle. The strength of SAC and its modulation by cell fate and size resemble SAC control in non-chordate embryos.
Review
Cell Biology
Yuqing Zhang, Chunlin Song, Lei Wang, Hongfei Jiang, Yujing Zhai, Ying Wang, Jing Fang, Gang Zhang
Summary: This review summarizes the research progress on the role of Bub1 in mitosis over the past three decades. The studies have revealed that Bub1 plays important roles in checkpoint regulation and chromosome alignment. The essentiality of Bub1 in higher eukaryotic cells is discussed, along with some unresolved questions raised for future study.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sikai Liu, Xiao Yuan, Ping Gui, Ran Liu, Olanrewaju Durojaye, Donald L. Hill, Chuanhai Fu, Xuebiao Yao, Zhen Dou, Xing Liu
Summary: In mitosis, the interaction between Cyclin B2 and Mad2 guides accurate chromosome segregation through their localization at the kinetochores.
Review
Biochemistry & Molecular Biology
Shelby L. McVey, Jenna K. Cosby, Natalie J. Nannas
Summary: Accurate segregation of chromosomes is crucial for the survival of organisms and cells, and tension plays a key role in this process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Kyoko Okada, Bharat R. Iyer, Lindsay G. Lammers, Pedro A. Gutierrez, Wenzhe Li, Steven M. Markus, Richard J. Mckenney
Summary: This study reveals previously unknown steps in the activation pathway of cytoplasmic dynein-mediated cargo transport and provides insight into the integrated activities of LIS1/Ndel1 and dynactin/cargo-adapters. The findings contribute to the understanding of the roles of the human disease genes Ndel1 and LIS1 in the assembly and activation of dynein transport complexes.
NATURE COMMUNICATIONS
(2023)
Article
Engineering, Biomedical
Rumana Rashid, Yu-An Chen, John Hoffer, Jeremy L. Muhlich, Jia-Ren Lin, Robert Krueger, Hanspeter Pfister, Richard Mitchell, Sandro Santagata, Peter K. Sorger
Summary: This Perspective discusses the importance of the software ecosystem for tissue image analysis and emphasizes the need for interactive online guides to help histopathologists make complex images understandable to non-specialists. The concept of software interfaces like Minerva, which integrates multi-omic and tissue-atlas features and can be accessed via web browsers, is introduced to effectively disseminate digital histology data and aid their interpretation.
NATURE BIOMEDICAL ENGINEERING
(2022)
Article
Biology
Sanja Vickovic, Denis Schapiro, Konstantin Carlberg, Britta Lotstedt, Ludvig Larsson, Franziska Hildebrandt, Marina Korotkova, Aase H. Hensvold, Anca Catrina, Peter K. Sorger, Vivianne Malmstrom, Aviv Regev, Patrik L. Stahl
Summary: Spatial transcriptomics is used to study the local interactions in synovial tissue of rheumatoid arthritis patients. The results provide valuable insights into the spatial organization of cell populations and inflammation associated with rheumatoid arthritis.
COMMUNICATIONS BIOLOGY
(2022)
Meeting Abstract
Oncology
Kenichi Shimada, Yvonne X. Cui, Jonathan S. Goldberg, Ricardo Pastorello, Janae Davis, Tuulia Vallius, Lukas Kania, Ashka Patel, Mckenna Moore, Esther R. Ogayo, Deborah Dillon, Peter K. Sorger, Jennifer L. Guerriero, Elizabeth A. Mittendorf
Meeting Abstract
Oncology
Jennifer L. Guerriero, Gregory J. Baker, Jia-Ren Lin, Yu-An Chen, Ricardo Pastorello, Tuulia Vallius, Janae Davis, Clarence Yapp, Sarah E. Church, Eric Miller, Anniina Farkkila, Shaveta Vinayak, Melinda L. Telli, Giulia Fulci, Alan D'Andrea, Geoffrey I. Shapiro, Sara M. Tolaney, Sandro Santagata, Peter K. Sorger, Elizabeth A. Mittendorf
Article
Cell Biology
G. Kenneth Gray, Carman Man-Chung Li, Jennifer M. Rosenbluth, Laura M. Selfors, Nomeda Girnius, Jia-Ren Lin, Ron C. J. Schackmann, Walter L. Goh, Kaitlin Moore, Hana K. Shapiro, Shaolin Mei, Kurt D'Andrea, Katherine L. Nathanson, Peter K. Sorger, Sandro Santagata, Aviv Regev, Judy E. Garber, Deborah A. Dillon, Joan S. Brugge
Summary: This study presents a high-resolution breast atlas by integrating various techniques, defining different types of breast cells and their associations with breast cancer risk factors. A subset of cells associated with basal-like breast cancer was identified, and molecular factors regulating cell proportions were identified.
DEVELOPMENTAL CELL
(2022)
Article
Multidisciplinary Sciences
Giulia Notarangelo, Jessica B. Spinelli, Elizabeth M. Perez, Gregory J. Baker, Kiran Kurmi, Ilaria Elia, Sylwia A. Stopka, Gerard Baquer, Jia-Ren Lin, Alexandra J. Golby, Shakchhi Joshi, Heide F. Baron, Jefte M. Drijvers, Peter Georgiev, Alison E. Ringel, Elma Zaganjor, Samuel K. McBrayer, Peter K. Sorger, Arlene H. Sharpe, Kai W. Wucherpfennig, Sandro Santagata, Nathalie Y. R. Agar, Mario L. Suva, Marcia C. Haigis
Summary: Gain-of-function mutations in IDH result in the production of oncometabolite D-2HG, which promotes tumorigenesis by affecting the metabolism and antitumor functions of CD8(+) T cells.
Article
Oncology
Guihong Wan, Nga Nguyen, Feng Liu, Mia S. DeSimone, Bonnie W. Leung, Ahmad Rajeh, Michael R. Collier, Min Seok Choi, Munachimso Amadife, Kimberly Tang, Shijia Zhang, Jordan S. Phillipps, Ruple Jairath, Nora A. Alexander, Yining Hua, Meng Jiao, Wenxin Chen, Diane Ho, Stacey Duey, Istvan Balazs Nemeth, Gyorgy Marko-Varga, Jeovanis Gil Valdes, David Liu, Genevieve M. Boland, Alexander Gusev, Peter K. Sorger, Kun-Hsing Yu, Yevgeniy R. Semenov
Summary: This study assesses the effectiveness of machine-learning algorithms in predicting melanoma recurrence based on clinical and histopathologic features. The results show that machine-learning algorithms can extract predictive signals from these features and achieve high prediction performance, enabling the identification of patients who may benefit from adjuvant immunotherapy.
NPJ PRECISION ONCOLOGY
(2022)
Article
Biology
Sean M. Gross, Mark A. Dane, Rebecca L. Smith, Kaylyn L. Devlin, Ian C. McLean, Daniel S. Derrick, Caitlin E. Mills, Kartik Subramanian, Alexandra B. London, Denis Torre, John Erol Evangelista, Daniel J. B. Clarke, Zhuorui Xie, Cemal Erdem, Nicholas Lyons, Ted Natoli, Sarah Pessa, Xiaodong Lu, James Mullahoo, Jonathan Li, Miriam Adam, Brook Wassie, Moqing Liu, David F. Kilburn, Tiera A. Liby, Elmar Bucher, Crystal Sanchez-Aguila, Kenneth Daily, Larsson Omberg, Yunguan Wang, Connor Jacobson, Clarence Yapp, Mirra Chung, Dusica Vidovic, Yiling Lu, Stephan Schurer, Albert Lee, Ajay Pillai, Aravind Subramanian, Malvina Papanastasiou, Ernest Fraenkel, Heidi S. Feiler, Gordon B. Mills, Jake D. Jaffe, Avi Ma'ayan, Marc R. Birtwistle, Peter K. Sorger, James E. Korkola, Joe W. Gray, Laura M. Heiser
Summary: The phenotype and molecular state of a cell are influenced by external signals, and dysregulation of these signals can lead to various diseases. To understand the relationship between molecular and phenotypic changes, researchers have generated a comprehensive dataset that documents the transcriptional, proteomic, epigenomic, and phenotypic responses of MCF10A mammary epithelial cells after exposure to different ligands. This dataset serves as a valuable resource for the scientific community to gain biological insights, compare signals across different molecular modalities, and develop new computational methods for data analysis.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jia-Ren Lin, Shu Wang, Shannon Coy, Yu -An Chen, Clarence Yapp, Madison Tyler, Maulik K. Nariya, Cody N. Heiser, Ken S. Lau, Sandro Santagata, Peter K. Sorger
Summary: We used advanced imaging techniques, 3D reconstruction, spatial statistics, and machine learning to identify cell types and states associated with diagnostic and prognostic features in colorectal cancer. We found that at the tumor invasive margin, T cell suppression involves multiple cell types and that seemingly localized features such as tertiary lymphoid structures are interconnected and have graded molecular properties. These findings challenge the notion that discrete changes in tumor state are most important, demonstrating the presence of large-scale morphological and molecular gradients.
Article
Biochemistry & Molecular Biology
Fabian Froehlich, Luca Gerosa, Jeremy Muhlich, Peter K. Sorger
Summary: In this article, the mechanisms of adaptive rewiring in BRAF(V600E) melanoma cells were studied using an energy-based implementation of ordinary differential equation (ODE) modeling in combination with proteomic, transcriptomic and imaging data. Two parallel MAPK reaction channels were identified, which showed differential sensitivity to RAF and MEK inhibitors due to differences in protein oligomerization and drug binding. The study also revealed the time scale separation between immediate-early signaling and transcriptional feedback, creating a state in which the RAS-regulated MAPK channel can be activated by growth factors under conditions of fully inhibited BRAF(V600E)-driven channel. Further development of the approaches in this article is expected to yield a unified model of adaptive drug resistance in melanoma.
MOLECULAR SYSTEMS BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Caitlin E. Mills, Kartik Subramanian, Marc Hafner, Mario Niepel, Luca Gerosa, Mirra Chung, Chiara Victor, Benjamin Gaudio, Clarence Yapp, Ajit J. Nirmal, Nicholas Clark, Peter K. Sorger
Summary: The authors report a dye drop method using sequential density displacement and microscopy for multi-step assays on living cells. They used this method to collect single-cell dose-response data for small molecules in breast cancer cells. The dye drop method is rapid, reproducible, customizable, and enables the collection of information-rich perturbagen-response datasets.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Clarence Yapp, Edward Novikov, Won-Dong Jang, Tuulia Vallius, Yu-An Chen, Marcelo Cicconet, Zoltan Maliga, Connor A. Jacobson, Donglai Wei, Sandro Santagata, Hanspeter Pfister, Peter K. Sorger
Summary: This paper reports two findings that substantially improve image segmentation of tissues using a range of machine learning architectures. The inclusion of intentionally defocused and saturated images in training data and imaging the nuclear envelope using an antibody cocktail both significantly improve segmentation. These approaches have a positive impact on a wide range of tissue types and may have applications in image processing outside of microscopy.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
John A. Bachman, Benjamin M. Gyori, Peter K. Sorger
Summary: This study presents an approach to accurately assemble molecular mechanisms by using multiple natural language processing systems and INDRA, which improves the reliability of machine reading and assembles non-redundant mechanistic knowledge. Through this approach, the study extends protein-protein interaction databases and provides explanations for co-dependencies in the Cancer Dependency Map.
MOLECULAR SYSTEMS BIOLOGY
(2023)
Article
Chemistry, Medicinal
Changchang Liu, Peter Kutchukian, Nhan D. Nguyen, Mohammed AlQuraishi, Peter K. Sorger
Summary: This study presents a computational approach for qualitative and quantitative kinome-wide binding measurements using structure-based machine learning. The approach outperforms methods trained on crystal structures alone and structure-free methods in predicting kinase-compound interaction affinities. It also successfully captures known kinase biochemistry and generalizes well to distant kinase sequences and compound scaffolds.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Meeting Abstract
Oncology
Meri Rogava, Johannes C. Melms, Stephanie Davis, Clemens Hug, Bryan Ngo, Michael J. Lee, Patricia Ho, Amit Dipak Amin, Yiping Wang, Sean Chen, William Ge, David Liu, Thomas Tuting, Martin Rocken, Thomas K. Eigentler, Samuel F. Bakhoum, Andrei Molotkov, Akiva Mintz, Lewis C. Cantley, Peter K. Sorger, Benjamin Izar