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#39519037   2024/10/25 To Up

MAD2L2 Dimerization Is Not Essential for Mitotic Regulation.

MAD2L2 is a small HORMA domain protein that plays a crucial role in DNA repair and mitosis. In both TLS and shieldin, the dimerization of MAD2L2 via its HORMA domain is critical for the stability and function of these complexes. However, in mitosis, the dimerization state of MAD2L2 remains unknown. To assess the importance of MAD2L2's dimerization during mitosis, we utilized CRISPR/Cas9 to generate MAD2L2 knockout cells, which were subsequently complemented with MAD2L2 species carrying different dimer-disrupting point mutations. We assessed the ability of these MAD2L2 dimer-disrupting mutants to regulate mitosis by evaluating early mitotic events and mitotic fidelity. Our findings indicate that MAD2L2 can function in its monomeric form during mitosis, suggesting that MAD2L2 homodimerization is dispensable for early mitotic regulation. Furthermore, our results suggest that the binding of CDH1 to MAD2L2 is a key regulating factor in mitosis that may actively prevent the formation of MAD2L2 dimers, thereby shifting the cellular balance toward MAD2L2-CDH1 interaction. Thus, the equilibrium between the monomeric and dimeric forms of MAD2L2 is an important cellular factor regulating the MAD2L2-containing complexes.
Nomi Barda, Philippa Jennifer Ayiku, Amit Bar-On, Sahar Movshovitz, Tamar Listovsky

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#39475241   2024/10/30 To Up

On the possibility of yet a third kinetochore system in the protist phylum Euglenozoa.

Transmission of genetic material from one generation to the next is a fundamental feature of all living cells. In eukaryotes, a macromolecular complex called the kinetochore plays crucial roles during chromosome segregation by linking chromosomes to spindle microtubules. Little is known about this process in evolutionarily diverse protists. Within the supergroup Discoba, Euglenozoa forms a speciose group of unicellular flagellates-kinetoplastids, euglenids, and diplonemids. Kinetoplastids have an unconventional kinetochore system, while euglenids have subunits that are conserved among most eukaryotes. For diplonemids, a group of extremely diverse and abundant marine flagellates, it remains unclear what kind of kinetochores are present. Here, we employed deep homology detection protocols using profile-versus-profile Hidden Markov Model searches and AlphaFold-based structural comparisons to detect homologies that might have been previously missed. Interestingly, we still could not detect orthologs for most of the kinetoplastid or canonical kinetochore subunits with few exceptions including a putative centromere-specific histone H3 variant (cenH3/CENP-A), the spindle checkpoint protein Mad2, the chromosomal passenger complex members Aurora and INCENP, and broadly conserved proteins like CLK kinase and the meiotic synaptonemal complex proteins SYCP2/3 that also function at kinetoplastid kinetochores. We examined the localization of five candidate kinetochore-associated proteins in the model diplonemid, CENP-A shows discrete dots in the nucleus, implying that it is likely a kinetochore component. Mad2, CLK, SYCP2L1, and INCENP reside in the nucleus, but no clear kinetochore localization was observed. Altogether, these results point to the possibility that diplonemids evolved a hitherto unknown type of kinetochore system.
Corinna Benz, Maximilian W D Raas, Pragya Tripathi, Drahomíra Faktorová, Eelco C Tromer, Bungo Akiyoshi, Julius Lukeš

1593 related Products with: On the possibility of yet a third kinetochore system in the protist phylum Euglenozoa.

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#39470543   // To Up

Unveiling novel prognostic biomarkers and therapeutic targets for HBV-associated hepatocellular carcinoma through integrated bioinformatic analysis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, with limited treatment options. The goal of this study was to use integrated bioinformatic analysis to find possible biomarkers for prognosis and therapeutic targets for hepatitis B (HBV)-associated HCC. Three microarray datasets (GSE84402, GSE121248, and E-GEOD-19665) from patients with HBV-associated HCC were combined and analyzed. We identified differentially expressed genes (DEGs) and performed pathway enrichment analysis. We constructed protein-protein interaction networks to identify hub genes. We identified a total of 374 DEGs, which included 90 up-regulated and 284 down-regulated genes. Pathway enrichment analysis revealed associations with cell cycle, oocyte meiosis, and the p53 signaling pathway for up-regulated DEGs. Twenty hub genes were identified, and 9 of them (ZWINT, MELK, DLGAP5, BIRC5, AURKA, HMMR, CDK1, TTK, and MAD2L1) were validated using the Cancer Genome Atlas data and Kaplan-Meier survival analysis. These genes were significantly associated with a poor prognosis in HCC patients. Our research shows that ZWINT, MELK, DLGAP5, BIRC5, AURKA, HMMR, CDK1, TTK, and MAD2L1 may be useful for predicting how HBV-associated HCC will progress and for finding new ways to treat it. In addition to these further studies are needed to elucidate the functions of the remaining 11 identified hub genes (RRM2, NUSAP1, PBK, CCNB1, CCNB2, BUB1B, NEK2, CENPF, ASPM, TOP2A, and BUB1) in HCC development and progression.
Xue Ren, Niaoniao Feng

2804 related Products with: Unveiling novel prognostic biomarkers and therapeutic targets for HBV-associated hepatocellular carcinoma through integrated bioinformatic analysis.



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#39404369   2024/09/25 To Up

Dysfunction of Telomeric Cdc13-Stn1-Ten1 Simultaneously Activates DNA Damage and Spindle Checkpoints.

Telomeres, the ends of eukaryotic linear chromosomes, are composed of repeated DNA sequences and specialized proteins, with the conserved telomeric Cdc13/CTC1-Stn1-Ten1 (CST) complex providing chromosome stability via telomere end protection and the regulation of telomerase accessibility. In this study, , coding for a SUMO E3 ligase, and (a SUMO target for Siz1 and Siz2) were isolated as extragenic suppressors of CST temperature-sensitive mutants. -, - and - mutants were isolated next due to being sensitive to intracellular Siz1 dosage. In parallel, strong negative genetic interactions between mutants of CST and septins were identified, with septins being noticeably sumoylated through the action of Siz1. The temperature-sensitive arrest in these new mutants of CST was dependent on the G2/M Mad2-mediated and Bub2-mediated spindle checkpoints as well as on the G2/M Mec1-mediated DNA damage checkpoint. Our data suggest the existence of yet unknown functions of the telomeric Cdc13-Stn1-Ten1 complex associated with mitotic spindle positioning and/or assembly that could be further elucidated by studying these new -, - and - mutants.
Nathalie Grandin, Michel Charbonneau

2396 related Products with: Dysfunction of Telomeric Cdc13-Stn1-Ten1 Simultaneously Activates DNA Damage and Spindle Checkpoints.

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#39366534   2024/10/02 To Up

HNRNPD/MAD2L2 axis facilitates lung adenocarcinoma progression and is a potential prognostic biomarker.

Although progress has been made in the treatment of LAUD, the survival rate for patients remains poor. An in-depth grasp of the molecular pathways implicated in LUAD progression is vital for improving diagnosis and treatment strategies. This study aims to explore novel molecular mechanisms driving LUAD progression and identify new potential prognostic biomarkers for LAUD patients.
Zhuoyu Gu, Weizheng Ding, Shuang Yuan, Youqiang Peng, Bo Dong, Yike Gu, Jing Li, Yitong Chen, Kailu Wang, Tianze Liu, Xiaodan Han, Yixin Li

1679 related Products with: HNRNPD/MAD2L2 axis facilitates lung adenocarcinoma progression and is a potential prognostic biomarker.

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#39366370   2024/10/03 To Up

Probing hot spots of protein-protein interactions mediated by the safety-belt region of REV7.

REV7 is a HORMA (Hop1, Rev7, Mad2) family adaptor protein best known as an accessory subunit of the translesion synthesis (TLS) DNA polymerase ζ (Polζ). In this role, REV7 binds REV3, the catalytic subunit of Polζ, by locking REV7-binding motifs (RBMs) in REV3 underneath the REV7 safety-belt loop. The same mechanism is used by REV7 to interact with RBMs from other proteins in DNA damage response (DDR) and mitosis. Because of the importance of REV7 for TLS and other DDR pathways, targeting REV7:RBM protein-protein interactions (PPIs) with small molecules has emerged as a strategy to enhance cancer response to genotoxic chemotherapy. To identify druggable pockets at the REV7:RBM interface, we performed computational analyses of REV7 complexed with several RBM partners. The contributions of different interface regions to REV7:RBM stabilization were corroborated experimentally. These studies provide insights into key intermolecular interactions and establish targetable regions of REV7 for the design of REV7:RBM PPI inhibitors.
Radha Charan Dash, Gianluca A Arianna, Seema M Patel, Alessandro A Rizzo, Noah J Harrahill, Dmitry M Korzhnev, M Kyle Hadden

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#39102671   // To Up

Analysis of translesion polymerases in colorectal cancer cells following cetuximab treatment: A network perspective.

Adaptive mutagenesis observed in colorectal cancer (CRC) cells upon exposure to EGFR inhibitors contributes to the development of resistance and recurrence. Multiple investigations have indicated a parallel between cancer cells and bacteria in terms of exhibiting adaptive mutagenesis. This phenomenon entails a transient and coordinated escalation of error-prone translesion synthesis polymerases (TLS polymerases), resulting in mutagenesis of a magnitude sufficient to drive the selection of resistant phenotypes.
Anubrata Das, Georgios V Gkoutos, Animesh Acharjee

2826 related Products with: Analysis of translesion polymerases in colorectal cancer cells following cetuximab treatment: A network perspective.



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#39079532   2024/07/29 To Up

Distinct roles of spindle checkpoint proteins in meiosis.

Gametes are produced via meiosis, a specialized cell division associated with frequent errors that cause birth defects and infertility. Uniquely in meiosis I, homologous chromosomes segregate to opposite poles, usually requiring their linkage by chiasmata, the products of crossover recombination. The spindle checkpoint delays cell-cycle progression until all chromosomes are properly attached to microtubules, but the steps leading to the capture and alignment of chromosomes on the meiosis I spindle remain poorly understood. In budding yeast meiosis I, Mad2 and Mad3 are equally important for spindle checkpoint delay, but biorientation of homologs on the meiosis I spindle requires Mad2, but not Mad3. Here we reveal the distinct functions of Mad2 and Mad3 in meiosis I chromosome segregation. Mad2 promotes the prophase to metaphase I transition, while Mad3 associates with the TOGL1 domain of Stu1, a conserved plus-end microtubule protein that is important for chromosome capture onto the spindle. Homologous chromosome pairs that are proficient in crossover formation but fail to biorient rely on Mad3-Stu1 to ensure their efficient attachment to microtubules and segregation during meiosis I. Furthermore, we show that Mad3-Stu1 are essential to rescue the segregation of mini-chromosomes lacking crossovers. Our findings define a new pathway ensuring microtubule-dependent chromosome capture and demonstrate that spindle checkpoint proteins safeguard the fidelity of chromosome segregation both by actively promoting chromosome alignment and by delaying cell-cycle progression until this has occurred.
Anuradha Mukherjee, Christos Spanos, Adele L Marston

2879 related Products with: Distinct roles of spindle checkpoint proteins in meiosis.

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#39056737   2024/07/19 To Up

Transcriptome Analysis of Transiently Reversible Cell Vacuolization Caused by Excessive Serum Concentration in .

As an important research tool, cell lines play a vital role in life science research, medical research, and drug development. During the culture of the head kidney (TK) cell line, we found a phenomenon of cell vacuolization caused by excessive serum concentration. Moreover, the vacuolization of the cells gradually disappeared after passage by trypsin digestion. In clarifying the formation mechanism of this reversible cellular vacuolation, transcriptomics was utilized to explore the mechanism of cell vacuolization caused by excessive serum concentration. Transcriptome analysis indicated that excessive serum concentration could cause the up-regulated expression of PORCN and other genes to promote cell proliferation. Compared with cells whose vacuolization disappeared after trypsin digestion and passage, the expression of mitosis-related genes (BUB1, ttk, Mad2, Cdc20, CDK1, CCNB1), nuclear stability-related genes LMNB1 and tissue stress and repair-related genes HMMR in vacuolated cells caused by excessive serum concentration was significantly up-regulated. There is a regulatory system related to adaptation and stress repair in the cells, which can maintain cell stability to a certain extent. This study provides a theoretical basis for the stable culture of fish cell lines and the solution to the problem of cell vacuolation.
Yuting Song, Lijun Shao, Xiaoli Yu

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