bims-micesi 2024-06-30 papers

Issue of 2024–06–30
four papers selected by
Valentina Piano, Uniklinik Köln

Int J Mol Sci. 2024 Jun 07. pii: 6329. [Epub ahead of print]25(12):

Suppressing Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 Activity to Enhance the Effectiveness of Anti-Cancer Drugs That Induce Multipolar Mitotic Spindles.

Scott C Schuyler, Hsin-Yu Chen, Kai-Ping Chang.

Paclitaxel induces multipolar spindles at clinically relevant doses but does not substantially increase mitotic indices. Paclitaxel's anti-cancer effects are hypothesized to occur by promoting chromosome mis-segregation on multipolar spindles leading to apoptosis, necrosis and cyclic-GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) pathway activation in daughter cells, leading to secretion of type I interferon (IFN) and immunogenic cell death. Eribulin and vinorelbine have also been reported to cause increases in multipolar spindles in cancer cells. Recently, suppression of Anaphase-Promoting Complex/Cyclosome-Cell Division Cycle 20 (APC/C-CDC20) activity using CRISPR/Cas9 mutagenesis has been reported to increase sensitivity to Kinesin Family 18a (KIF18a) inhibition, which functions to suppress multipolar mitotic spindles in cancer cells. We propose that a way to enhance the effectiveness of anti-cancer agents that increase multipolar spindles is by suppressing the APC/C-CDC20 to delay, but not block, anaphase entry. Delaying anaphase entry in genomically unstable cells may enhance multipolar spindle-induced cell death. In genomically stable healthy human cells, delayed anaphase entry may suppress the level of multipolar spindles induced by anti-cancer drugs and lower mitotic cytotoxicity. We outline specific combinations of molecules to investigate that may achieve the goal of enhancing the effectiveness of anti-cancer agents.

Keywords: anaphase-promoting complex/cyclosome (APC/C); cancer; cell division cycle 20 (CDC20); paclitaxel

DOI: https://doi.org/10.3390/ijms25126329

Nat Commun. 2024 Jun 25. 15(1): 5381

Shape of the first mitotic spindles impacts multinucleation in human embryos.

Yuki Ono, Hiromitsu Shirasawa, Kazumasa Takahashi, Mayumi Goto, Takahiro Ono, Taichi Sakaguchi, Motonari Okabe, Takeo Hirakawa, Takuya Iwasawa, Akiko Fujishima, Tae Sugawara, Kenichi Makino, Hiroshi Miura, Noritaka Fukunaga, Yoshimasa Asada, Yukiyo Kumazawa, Yukihiro Terada.

During human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we image discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigate the association between spindle shape and nuclear abnormality during the first mitosis. We observe that the first mitotic spindles vary, and low-aspect-ratio-shaped spindles tend to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observe defocusing poles in many of the first mitotic spindles, which are strongly associated with multinucleation. Additionally, we show that differences in the positions of the centrosomes cause spindle abnormality in the first mitosis. Furthermore, many multinuclei are modified to form mononuclei after the second mitosis because the occurrence of pole defocusing is firmly reduced. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos.

DOI: https://doi.org/10.1038/s41467-024-49815-8

Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2317316121

An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.

In-Won Lee, Abbas Pirpour Tazehkand, Zi-Yi Sha, Deepak Adhikari, John Carroll.

A dispersed cytoplasmic distribution of mitochondria is a hallmark of normal cellular organization. Here, we have utilized the expression of exogenous Trak2 in mouse oocytes and embryos to disrupt the dispersed distribution of mitochondria by driving them into a large cytoplasmic aggregate. Our findings reveal that aggregated mitochondria have minimal impact on asymmetric meiotic cell divisions of the oocyte. In contrast, aggregated mitochondria during the first mitotic division result in daughter cells with unequal sizes and increased micronuclei. Further, in two-cell embryos, microtubule-mediated centering properties of the mitochondrial aggregate prevent nuclear centration, distort nuclear shape, and inhibit DNA synthesis and the onset of embryonic transcription. These findings demonstrate the motor protein-mediated distribution of mitochondria throughout the cytoplasm is highly regulated and is an essential feature of cytoplasmic organization to ensure optimal cell function.

Keywords: Meiosis; Mitosis; Nuclear morphology; TRAK2; mitochondrial aggregation

DOI: https://doi.org/10.1073/pnas.2317316121

EMBO Rep. 2024 Jun 28.

Spermatocytes have the capacity to segregate chromosomes despite centriole duplication failure.

Marnie W Skinner, Carter J Simington, Pablo López-Jiménez, Kerstin A Baran, Jingwen Xu, Yaron Dayani, Marina V Pryzhkova, Jesús Page, Rocío Gómez, Andrew J Holland, Philip W Jordan.

Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility.

Keywords: Centriole; Centrosome; Meiosis; PLK4; Spermatogenesis

DOI: https://doi.org/10.1038/s44319-024-00187-6