bims-micesi 2024-05-05 papers

Issue of 2024‒05‒05
five papers selected by
Valentina Piano, Uniklinik Köln

Bioinform Biol Insights. 2024 ;18 11779322241248913

Analysis of CENP-B Boxes as Anchor of Kinetochores in Centromeres of Human Chromosomes.

The kinetochore is a multiprotein structure that attaches at one end to DNA in the centromere and at the other end to microtubules in the mitotic spindle. By connecting centromere and spindle, the kinetochore controls the migration of chromosomes during cell division. The exact position where the kinetochore assembles on each centromere was uncertain because large sections of centromeric DNA had not been sequenced due to highly repetitive alpha-satellite arrays. Embedded in the arrays is a 17 bp consensus sequence, the so-called CENP-B box, which binds the CENP-B protein, the only protein that binds directly to centromeric DNA. Recently, the Telomere-to-Telomere Consortium published the complete centromeric DNA sequences of all chromosomes including their epigenetic modifications in the T2T-CHM13 map. I used data from the T2T-CHM13 map to locate the CENP-B boxes in the centromeres as anchor of kinetochores. Most of the CENP-B boxes in centromeric DNA are methylated with the exception of the so-called centromere dip region (CDR), where CENP-B protein dimers bind to adjacent unmethylated CENP-B boxes and interact with CENP-A and CENP-C proteins to assemble the kinetochore. The centromeres of all chromosomes combined have a size of 407 Mb of which the kinetochores account for 5.0 Mb or 1.2%. There is no correlation between centromere and kinetochore size (P = .77). While the number of CENP-B boxes varies 4-fold between chromosomes, their density (number/Kb) varies less than 2-fold with a mean of 2.61 ± 0.33. The narrow range ensures a uniform pull of the spindle on the centromeres. I illustrate the findings in a model of the human kinetochore anchored at unmethylated CENP-B boxes in the CDR and present circos plots of chromosomes to show the location of kinetochores in their respective centromeres.

Keywords: Human genome; centromere; chromosome; kinetochore

DOI: https://doi.org/10.1177/11779322241248913

Cell Rep. 2024 Apr 27. pii: S2211-1247(24)00483-2. [Epub ahead of print]43(5): 114155

CDK1-PP2A-B55 interplay ensures cell cycle oscillation via Apc1-loop300.

Kim Hou Chia, Hiroko Takaki, Kazuyuki Fujimitsu, Sarah Darling, Juan Zou, Juri Rappsilber, Hiroyuki Yamano.

Cell cycle control relies on a delicate balance of phosphorylation with CDK1 and phosphatases like PP1 and PP2A-B55. Yet, identifying the primary substrate responsible for cell cycle oscillations remains a challenge. We uncover the pivotal role of phospho-regulation in the anaphase-promoting complex/cyclosome (APC/C), particularly through the Apc1-loop300 domain (Apc1-300L), orchestrated by CDK1 and PP2A-B55. Premature activation of PP2A-B55 during mitosis, induced by Greatwall kinase depletion, leads to Apc1-300L dephosphorylation, stalling APC/C activity and delaying Cyclin B degradation. This effect can be counteracted using the B55-specific inhibitor pEnsa or by removing Apc1-300L. We also show Cdc20's dynamic APC/C interaction across cell cycle stages, but dephosphorylation of Apc1-300L specifically inhibits further Cdc20 recruitment. Our study underscores APC/C's central role in cell cycle oscillation, identifying it as a primary substrate regulated by the CDK-PP2A partnership.

Keywords: APC/C; CDK; CP: Cell biology; CP: Molecular biology; Cdc20; Cell cycle; PP2A-B55; intrinsically disordered regions; mitosis; phosphatase; phosphorylation; ubiquitin ligase

DOI: https://doi.org/10.1016/j.celrep.2024.114155

Adv Sci (Weinh). 2024 Apr 29. e2308690

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

Rendy Hosea, Wei Duan, Ian Timothy Sembiring Meliala, Wenfang Li, Mankun Wei, Sharon Hillary, Hezhao Zhao, Makoto Miyagishi, Shourong Wu, Vivi Kasim.

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly understood. Here, using a cross-omics approach, YY2 is identified as a mitotic regulator that promotes SAC activity by activating the transcription of budding uninhibited by benzimidazole 3 (BUB3), a component of SAC. While both conditions induce CIN, a defect in YY2/SAC activity enhances mitosis and tumor growth. Meanwhile, hyperactivation of SAC mediated by YY2/BUB3 triggers a delay in mitosis and suppresses growth. Furthermore, it is revealed that YY2/BUB3-mediated excessive CIN causes higher cell death rates and drug sensitivity, whereas residual tumor cells that survived DNA damage-based therapy have moderate CIN and increased drug resistance. These results provide insights into the role of SAC activity and CIN levels in influencing tumor cell survival and drug response, as well as suggest a novel anti-tumor therapeutic strategy that combines SAC activity modulators and DNA-damage agents.

Keywords: chromosomal instability (CIN); drug resistance; mitosis; residual tumor cells; yin yang 2 (YY2)

DOI: https://doi.org/10.1002/advs.202308690

Proteins. 2024 May 03.

Crystal structure of human Cep57 C-terminal domain reveals the presence of leucine zipper and the potential microtubule binding region.

Sanskrita Sukla, Dhayanitha Ranganathan Dhakshinamoorthy, Arvind V Ramesh, Scott Lew, Min Su, Jayaraman Seetharaman.

Cep57, a vital centrosome-associated protein, recruits essential regulatory enzymes for centriole duplication. Its dysfunction leads to anomalies, including reduced centrioles and mosaic-variegated aneuploidy syndrome. Despite functional investigations, understanding structural aspects and their correlation with functions is partial till date. We present the structure of human Cep57 C-terminal microtubule binding (MT-BD) domain, revealing conserved motifs ensuring functional preservation across evolution. A leucine zipper, with an adjacent possible microtubule-binding region, potentially forms a stabilizing scaffold for microtubule nucleation-accommodating pulling and tension from growing microtubules. This study highlights conserved structural features of Cep57 protein, compares them with other analogous proteins, and explores how protein function is maintained across diverse organisms.

Keywords: coiled‐coil; evolution; leucine zipper; microtubule‐binding; structure

DOI: https://doi.org/10.1002/prot.26698

Mol Biol Cell. 2024 May 02. mbcE24020096T

Germ fate determinants protect germ precursor cell division by reducing septin and anillin levels at the cell division plane.

Caroline Q Connors, Michael S Mauro, J Tristian Wiles, Andrew D Countryman, Sophia L Martin, Benjamin Lacroix, Mimi Shirasu-Hiza, Julien Dumont, Karen E Kasza, Timothy R Davies, Julie C Canman.

Animal cell cytokinesis, or the physical division of one cell into two, is thought to be driven by constriction of an actomyosin contractile ring at the division plane. The mechanisms underlying cell type-specific differences in cytokinesis remain unknown. Germ cells are totipotent cells that pass genetic information to the next generation. Previously, using formincyk-1(ts) mutant C. elegans embryos, we found that the P2 germ precursor cell is protected from cytokinesis failure and can divide with greatly reduced F-actin levels at the cell division plane. Here, we identified two canonical germ fate determinants required for P2-specific cytokinetic protection: PIE-1 and POS-1. Neither has been implicated previously in cytokinesis. These germ fate determinants protect P2 cytokinesis by reducing the accumulation of septinUNC-59 and anillinANI-1 at the division plane, which here act as negative regulators of cytokinesis. These findings may provide insight into the regulation of cytokinesis in other cell types, especially in stem cells with high potency.

DOI: https://doi.org/10.1091/mbc.E24-02-0096-T