Role In Cell Division Research Articles

Integrated Analysis Reveals Genetic Basis of Growth Curve Parameters in an F2 Designed Pig Population Based on Genome and Transcriptome Data

Appropriate growth curves can reflect more sophisticated growth patterns of animals than body weight, and thus, the identification of genes and variants related to the growth curve parameter traits contributes to revealing the fine growth and development characteristics of livestock. However, the ability of single genome-wide association analysis (GWAS) and transcriptome analyses to identify valuable genes and variants is limited. In this study, based on genome and transcriptome data, the growth curve parameter traits of hybrid pigs were analyzed, and a set of genes and variants were identified. The Gompertz–Laird growth curve model was optimized to reveal the growth pattern of F2 individuals of Duroc × Erhualian pigs over four time points. Five growth parameters were estimated, including initial body weight (W0), instantaneous growth rate per day (L), coefficient of relative growth or maturing index (k), body weight at inflection point (Wi), and average growth rate (GR). These five parameters were subjected to a genome-wide association study, differential gene expression analysis, and weighted gene co-expression network analysis (WGCNA). In the study, 336 pigs were genotyped, and 39,494 SNP markers were used for each pig in the analysis. Thirty of these pigs were also included in the transcriptomics analysis. Based on genome and transcriptome data, the integrated analyses identified five putative SNPs (including INRA0056460 on chromosome X, DRGA0004151 on chromosome 3, INRA0056460 on chromosome X, H3GA0049324 on chromosome 17, and H3GA0037747 on chromosome 13) and 15 candidate genes (PDGFA, VEGFD, CSPP1, EFHC1, PIK3C3, ZZZ3, GCC2, MAPK14, ZPR1, ISG15, ANG, CEBPD, ZHX3, CTBP2, and MYNN). The functional analysis indicated that these candidate genes played important roles in cell division and differentiation, development and aging, and skeletal muscle and fat formation. Our results provide insight into the genetic mechanisms underlying the growth and development of hybrid pigs and offer a theoretical basis for genomic breeding.

A Comprehensive Review of Protein Biomarkers for Invasive Lung Cancer.

Invasion and metastasis are important hallmarks of lung cancer, and affect patients' survival. Early diagnostics of metastatic potential are important for treatment management. Recent findings suggest that the transition to an invasive phenotype causes changes in the expression of 700-800 genes. In this context, the biomarkers restricted to the specific type of cancer, like lung cancer, are often overlooked. Some well-known protein biomarkers correlate with the progression of the disease and the immunogenicity of the tumor. Most of these biomarkers are not exclusive to lung cancer because of their significant role in tumorigenesis. The dysregulation of others does not necessarily indicate cell invasiveness, as they play an active role in cell division. Clinical studies of lung cancer use protein biomarkers to assess the invasiveness of cancer cells for therapeutic purposes. However, there is still a need to discover new biomarkers for lung cancer. In the future, minimally invasive techniques, such as blood or saliva analyses, may be sufficient for this purpose. Many researchers suggest unconventional biomarkers, like circulating nucleic acids, exosomal proteins, and autoantibodies. This review paper aims to discuss the advantages and limitations of protein biomarkers of invasiveness in lung cancer, to assess their prognostic value, and propose novel biomarker candidates.

Abstract We030: Microtubule Organizing Centers in Cardiomyocyte Proliferation and Maturation

Mammalian cardiomyocytes undergo a loss of proliferative capacity due to cell division failure, leading to polyploidy (genome duplication) during postnatal maturation. Centrosomes, primary microtubule organizing centers (MTOCs) in animal cells comprised of centrioles and pericentriolar matrix (PCM), play a crucial role in cell division. In differentiated cells, non-centrosomal (nc) MTOCs can reorganize microtubules, with cellular localization varying between cell types to mediate specialized functions. The specific role of ncMTOCs in cardiomyocyte division and maturation remains unknown. This study investigates the formation and function of ncMTOCs in cardiomyocytes, aiming to elucidate the regulating mechanism. Our results demonstrate that during the maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), centrosomes disassemble, and their PCM translocates to the nuclear envelope, establishing perinuclear ncMTOCs. Furthermore, maturing CMs with ncMTOCs often exhibit polyploidy, indicating incomplete cell division. Microtubule dynamic experiments reveal that ncMTOCs serve as organizing centers for microtubules, promoting their assembly around the nucleus in maturing cardiomyocytes. To understand the mechanism regulating the transition from centrosomes to ncMTOCs in cardiomyocytes, we identified a significant downregulation of the nuclear lamina protein Lamin B2 (LMNB2) during CM maturation. Our results indicate that LMNB2 is essential for mitotic spindle formation in CMs but not in stem cells, suggesting a distinct role for LMNB2 in CMs. Our results also suggest an increased centrosome to ncMTOC transition in LMNB2-depleted CMs at an early differentiation stage. Ongoing research aims to investigate the impact of perinuclear ncMTOCs on cardiomyocyte proliferation through pericentriolar matrix knockdown in hiPSC-CMs. Additionally, the study seeks to further elucidate the role of Lamin B2 in the transition of centrosome proteins and its underlying mechanism.

MinD2 modulates cell shape and motility in the archaeon Haloferax volcanii.

In bacteria and archaea, proteins of the ParA/MinD family of ATPases regulate the spatiotemporal organization of various cellular cargoes, including cell division proteins, motility structures, chemotaxis systems, and chromosomes. In bacteria, such as Escherichia coli, MinD proteins are crucial for the correct placement of the Z-ring at mid-cell during cell division. However, previous studies have shown that none of the 4 MinD homologs present in the archaeon Haloferax volcanii have a role in cell division, suggesting that these proteins regulate different cellular processes in haloarchaea. Here, we show that while deletion of MinD2 in H. volcanii (ΔminD2) does not affect cell growth or division, it impacts cell shape and motility by mispositioning the chemotaxis arrays and archaellum motors. Finally, we explore the links between MinD2 and MinD4, which has been previously shown to modulate the localization of chemosensory arrays and archaella in H. volcanii, finding that the two MinD homologues have synergistic effects in regulating the positioning of the motility machinery. Collectively, our findings identify MinD2 as an important link between cell shape and motility in H. volcanii and further our understanding of the mechanisms by which multiple MinD proteins regulate cellular functions in haloarchaea.

Septins promote macrophage pyroptosis by regulating gasdermin D cleavage and ninjurin-1-mediated plasma membrane rupture

The septin cytoskeleton is primarily known for roles in cell division and host defense against bacterial infection. Despite recent insights, the full breadth of roles for septins in host defense is poorly understood. In macrophages, Shigella induces pyroptosis, a pro-inflammatory form of cell death dependent upon gasdermin D (GSDMD) pores at the plasma membrane and cell surface protein ninjurin-1 (NINJ1) for membrane rupture. Here, we discover that septins promote macrophage pyroptosis induced by lipopolysaccharide (LPS)/nigericin and Shigella infection, but do not affect cytokine expression or release. We observe that septin filaments assemble at the plasma membrane, and cleavage of GSDMD is impaired in septin-depleted cells. We found that septins regulate mitochondrial dynamics and the expression of NINJ1. Using a Shigella-zebrafish infection model, we show that septin-mediated pyroptosis is an invivo mechanism of infection control. The discovery of septins as a mediator of pyroptosis may inspire innovative anti-bacterial and anti-inflammatory treatments.

Non-Coding RNAs of Mitochondrial Origin: Roles in Cell Division and Implications in Cancer.

Non-coding RNAs (ncRNAs) are a heterogeneous group, in terms of structure and sequence length, consisting of RNA molecules that do not code for proteins. These ncRNAs have a central role in the regulation of gene expression and are virtually involved in every process analyzed, ensuring cellular homeostasis. Although, over the years, much research has focused on the characterization of non-coding transcripts of nuclear origin, improved bioinformatic tools and next-generation sequencing (NGS) platforms have allowed the identification of hundreds of ncRNAs transcribed from the mitochondrial genome (mt-ncRNA), including long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miR). Mt-ncRNAs have been described in diverse cellular processes such as mitochondrial proteome homeostasis and retrograde signaling; however, the function of the majority of mt-ncRNAs remains unknown. This review focuses on a subgroup of human mt-ncRNAs whose dysfunction is associated with both failures in cell cycle regulation, leading to defects in cell growth, cell proliferation, and apoptosis, and the development of tumor hallmarks, such as cell migration and metastasis formation, thus contributing to carcinogenesis and tumor development. Here we provide an overview of the mt-ncRNAs/cancer relationship that could help the future development of new biomedical applications in the field of oncology.

Cell Division and Motility Enable Hexatic Order in Biological Tissues.

Biological tissues transform between solid- and liquidlike states in many fundamental physiological events. Recent experimental observations further suggest that in two-dimensional epithelial tissues these solid-liquid transformations can happen via intermediate states akin to the intermediate hexatic phases observed in equilibrium two-dimensional melting. The hexatic phase is characterized by quasi-long-range (power-law) orientational order but no translational order, thus endowing some structure to an otherwise structureless fluid. While it has been shown that hexatic order in tissue models can be induced by motility and thermal fluctuations, the role of cell division and apoptosis (birth and death) has remained poorly understood, despite its fundamental biological role. Here we study the effect of cell division and apoptosis on global hexatic order within the framework of the self-propelled Voronoi model of tissue. Although cell division naively destroys order and active motility facilitates deformations, we show that their combined action drives a liquid-hexatic-liquid transformation as the motility increases. The hexatic phase is accessed by the delicate balance of dislocation defect generation from cell division and the active binding of disclination-antidisclination pairs from motility. We formulate a mean-field model to elucidate this competition between cell division and motility and the consequent development of hexatic order.

Comprehensive identification of maize ZmE2F transcription factors and the positive role of ZmE2F6 in response to drought stress

BackgroundThe early 2 factor (E2F) family is characterized as a kind of transcription factor that plays an important role in cell division, DNA damage repair, and cell size regulation. However, its stress response has not been well revealed.ResultsIn this study, ZmE2F members were comprehensively identified in the maize genome, and 21 ZmE2F genes were identified, including eight E2F subclade members, seven DEL subfamily genes, and six DP genes. All ZmE2F proteins possessed the DNA-binding domain (DBD) characterized by conserved motif 1 with the RRIYD sequence. The ZmE2F genes were unevenly distributed on eight maize chromosomes, showed diversity in gene structure, expanded by gene duplication, and contained abundant stress-responsive elements in their promoter regions. Subsequently, the ZmE2F6 gene was cloned and functionally verified in drought response. The results showed that the ZmE2F6 protein interacted with ZmPP2C26, localized in the nucleus, and responded to drought treatment. The overexpression of ZmE2F6 enhanced drought tolerance in transgenic Arabidopsis with longer root length, higher survival rate, and biomass by upregulating stress-related gene transcription.ConclusionsThis study provides novel insights into a greater understanding and functional study of the E2F family in the stress response.

Discovery of novel octahydroquinazoline scaffolds endowed with dual inhibition of tubulin polymerization/Eg5 against HCC: Apoptotic and radio-chemotherapeutic studies

Mitotic kinesin Eg5 isozyme as a motor protein plays a critical role in cell division of tumor cells. Kinesin Eg5 selective inhibitors and Colchicine binding site suppressors are essential targets for many anticancer drugs and radio chemotherapies. On this work, a new series of octahydroquinazoline as anti-mitotic candidates 2–13 has been synthesized with dual inhibition of tubulin polymerization/Eg5 against HCC cell line. All octahydroquinazolines have been in vitro assayed against HepG-2 cytotoxicity, Eg5 inhibitory and anti-tubulin polymerization activities. The most active analogues 7, 8, 9, 10, and 12 against HepG-2 were further subjected to in vitro cytotoxic assay against HCT-116 and MCF-7 cell lines. Chalcones 9, 10, and 12 displayed the most cytotoxic potency and anti-tubulin aggregation in comparable with reference standard colchicine and potential anti-mitotic Eg5 inhibitory activity in comparison with Monastrol as well. Besides, they exhibited cell cycle arrest at the G2/M phase. Moreover, good convinced apoptotic activities have been concluded as overexpression of caspase-3 levels and tumor suppressive gene p53 in parallel with higher induction of Bax and inhibition of Bcl-2 biomarkers. Octahydroquinazoline 10 displayed an increase in caspase-3 by 1.12 folds compared to standard colchicine and induce apoptosis and demonstrated cell cycle arrest in G2/M phase arrest by targeting p53 pathway. Analogue 10 has considerably promoted cytotoxic radiation activity and boosted apoptotic induction in HepG-2 cells by 1.5 fold higher than standard colchicine.

Opposing polarity domains provide direction and play a role in cell division in plant growth

Polar localization of proteins is important for plant growth and development. Identifying the interactors of polarized proteins provides spatial information and cell-type functions. In this issue of Developmental Cell, Wallner etal. (2024) utilize opposing polarity domain proteins to identify interactors and their functions during cell division in Arabidopsis stomata.

Near telomere-to-telomere genome assemblies of two Chlorella species unveil the composition and evolution of centromeres in green algae

BackgroundCentromeres play a crucial and conserved role in cell division, although their composition and evolutionary history in green algae, the evolutionary ancestors of land plants, remains largely unknown.ResultsWe constructed near telomere-to-telomere (T2T) assemblies for two Trebouxiophyceae species, Chlorella sorokiniana NS4-2 and Chlorella pyrenoidosa DBH, with chromosome numbers of 12 and 13, and genome sizes of 58.11 Mb and 53.41 Mb, respectively. We identified and validated their centromere sequences using CENH3 ChIP-seq and found that, similar to humans and higher plants, the centromeric CENH3 signals of green algae display a pattern of hypomethylation. Interestingly, the centromeres of both species largely comprised transposable elements, although they differed significantly in their composition. Species within the Chlorella genus display a more diverse centromere composition, with major constituents including members of the LTR/Copia, LINE/L1, and LINE/RTEX families. This is in contrast to green algae including Chlamydomonas reinhardtii, Coccomyxa subellipsoidea, and Chromochloris zofingiensis, in which centromere composition instead has a pronounced single-element composition. Moreover, we observed significant differences in the composition and structure of centromeres among chromosomes with strong collinearity within the Chlorella genus, suggesting that centromeric sequence evolves more rapidly than sequence in non-centromeric regions.ConclusionsThis study not only provides high-quality genome data for comparative genomics of green algae but gives insight into the composition and evolutionary history of centromeres in early plants, laying an important foundation for further research on their evolution.

Molecular functions of ANKLE2 and its implications in human disease.

Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.

Abstract 3345: PP1 phosphatase complex at the hub of the integrated stress response: A potential therapeutic target in multiple myeloma

Abstract Protein phosphatase-1 (PP1) is a class of eukaryotic enzyme that catalyzes more than half of the phosphoserine/threonine dephosphorylation reactions, and plays essential roles in cell division, glycogen metabolism and protein synthesis. The substrate specificity of PP1 holoenzyme complex is mediated by PP1-interacting proteins and its catalytic subunits. Of note, PPP1R15B/CReP and PPP1R15A/GADD34 are regulatory subunits of PP1 complex that regulates global protein synthesis and mRNA translation through eIF2α dephosphorylation. Notably, PPP1R15B is constitutively expressed, whereas the expression of PPP1R15A is stress-inducible. Previous studies showed that multiple myeloma (MM), a hematological malignancy arising from immunoglobulin-secreting plasma cells, is characterized by continual ER stress and high dependency on the unfolded protein response (UPR). The integrated stress response (ISR) activated by eIF2α phosphorylation is the fastest reaction pathway of the UPR; however, its functional role and therapeutic potential in MM remains largely unknown. In this study, we performed gene expression analysis and super-enhancer (SE) profiling in MM cell lines, primary patient samples, normal CD138+ plasma cells and memory B cells. we found that PPP1R15B is highly expressed in MM cells as compared to healthy controls, but did not observe significant upregulation of PPP1R15A in MM cells. In addition, higher expression of PPP1R15B predicted poor overall survival of MM patients, suggesting its clinical relevance in MM pathogenesis. Depletion of PPP1R15B significantly reduced cell viability, proliferation and induced G2/M phase cell cycle arrest. Gene Ontology analysis of downregulated genes in response to PPP1R15B knockdown indicates significant association with the UPR pathway. Immunoblot analysis showed activation of ER stress pro-apoptotic executors PUMA, NOXA, and cleavage of caspase-12 in PPP1R15B knockdown cells. Furthermore, we examined the therapeutic effects of eIF2α dephosphorylation inhibitors, Salubrinal and Raphin1, on MM cells. Raphin1 is a selective inhibitor of PPP1R15B that binds strongly to the PPP1R15B-PP1c complex, whereas Salubrinal inhibits both PPP1R15A-PP1c and PPP1R15B-PP1c complex. Our data showed that both Salubrinal and Raphin1 inhibited MM cell proliferation in a dose-dependent manner, while sparing normal plasma cells. MM cell lines with elevated PPP1R15B expression level were more sensitive to Salubrinal or Raphin1 than those with lower PPP1R15B level. Similar changes in the expression patterns of ISR-related genes were observed in response to eIF2α dephosphorylation inhibitors. Taken together, our study suggests that targeting PPP1R15B-PP1c complex or maintaining eIF2α hyperphosphorylation may serve as a new therapeutic approach in MM, which warrants further investigation. Citation Format: Sinan Xiong, Jianbiao Zhou, Tze King Tan, Sabrina Hui-Min Toh, Tae-Hoon Chung, Takaomi Sanda, Wee Joo Chng. PP1 phosphatase complex at the hub of the integrated stress response: A potential therapeutic target in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3345.

Abstract 5723: Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay

Abstract Kinesin superfamily proteins (KIFs) are a large family of molecular motor proteins, that share a highly conserved motor domain. KIFs play an important role in cell division and transport of vesicles and organelles within cells. Mitotic kinesins hydrolyze ATP through its ATPase activity to move along the spindle microtubules and carry out several functions during mitosis to facilitate precise chromosome segregation. Altered expressions of several kinesins are shown in various cancers, fueling the aggressive nature of cancers leading to genomic instability. KIF11/Eg5 overexpression is shown in various cancers including hepatic carcinoma, lung, prostate, colorectal, gastric, and pancreatic cancers. Small molecule inhibitors of KIF11/Eg5 and CENP-E are shown to result in mitotic arrest leading to apoptosis in tumor cell lines. Despite the poor clinical outcome of several Eg5 and CENP-E inhibitors entered in clinical trials, targeting kinesins remains an attractive anti-cancer therapeutic approach. Recently, an inhibitor of KIF18A has entered clinical trial for treatment of solid tumors with high chromosomal instability. Here we show development of a microplate based biochemical screening assays for a panel of kinesin motor domain proteins. We summarize kinetic characterization of kinesin proteins and study the selectivity of various previously reported KIF18A, Eg5, CENP-E inhibitors across a kinesin selectivity panel. Citation Format: Brenna P. Lee, Sung Won Oh, Kurumi Y. Horiuchi, Safnas F. AbdulSalam. Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5723.

Abstract 4757: Combining PARP inhibitor with TACC3 inhibition overcomes PARP inhibitor resistance in ovarian cancer

Abstract The treatment of ovarian cancer (OC) presents a significant challenge due to the emergence of resistance to poly (ADP-ribose) polymerase inhibitors (PARPi). Transforming acidic coiled coil containing protein 3 (TACC3) belongs to the TACC family, characterized by its coiled-coil domains. TACC3 plays a crucial role in cell division, particularly in the formation and stability of the mitotic spindle, which is essential for proper chromosome segregation. Mutations or changes in TACC3 have been associated with various cancers, making it an increasingly attractive target for anticancer therapy in recent years. Here, we demonstrated a significant upregulation of TACC3 in OC, correlating with adverse clinical outcomes. Notably, PARPi-resistant OC cells exhibited a marked sensitivity to TACC3 inhibition. This was evidenced by the induction of spindle defects and mitotic catastrophe in PARPi-resistant cells upon TACC3 suppression, achieved either genetically or pharmacologically. Moreover, we explored the therapeutic efficacy of combining TACC3 inhibitor with PARPi, specifically BO-264 with olaparib or niraparib. This combination exhibited a synergistic effect, markedly reducing cell viability in vitro and tumor growth in PARPi-resistant tumor xenograft models. Our study suggests a promising new method for treating ovarian cancer, especially for those resistant to current PARPi treatments, by simultaneously targeting TACC3 and PARPi, enhancing treatment efficacy and potentially improving patient outcomes. Citation Format: Yu Wu, Qilong Wang, Chaolin Deng, Mo Li, Yinan Xiao. Combining PARP inhibitor with TACC3 inhibition overcomes PARP inhibitor resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4757.

The MoLfa1 Protein Regulates Fungal Development and Septin Ring Formation in Magnaporthe oryzae.

Septins play a key regulatory role in cell division, cytokinesis, and cell polar growth of the rice blast fungus (Magnaporthe oryzae). We found that the organization of the septin ring, which is essential for appressorium-mediated infection in M. oryzae, requires long-chain fatty acids (LCFAs), which act as mediators of septin organization at membrane interfaces. However, it is unclear how septin ring formation and LCFAs regulate the pathogenicity of the rice blast fungus. In this study, a novel protein was named MoLfa1 because of its role in LCFAs utilization. MoLfa1 affects the utilization of LCFAs, lipid metabolism, and the formation of the septin ring by binding with phosphatidylinositol phosphates (PIPs), thereby participating in the construction of penetration pegs of M. oryzae. In addition, MoLfa1 is localized in the endoplasmic reticulum (ER) and interacts with the ER-related protein MoMip11 to affect the phosphorylation level of Mps1. (Mps1 is the core protein in the MPS1-MAPK pathway.) In conclusion, MoLfa1 affects conidia morphology, appressorium formation, lipid metabolism, LCFAs utilization, septin ring formation, and the Mps1-MAPK pathway of M. oryzae, influencing pathogenicity.

Septin-dependent invasive growth by the rice blast fungus Magnaporthe oryzae

Septin GTPases are morphogenetic proteins that are widely conserved in eukaryotic organisms fulfilling diverse roles in cell division, differentiation and development. In the filamentous fungal pathogen Magnaporthe oryzae, the causal agent of the devastating blast diseases of rice and wheat, septins have been shown to be essential for plant infection. The blast fungus elaborates a specialised infection structure called an appressorium with which it mechanically ruptures the plant cuticle. Septin aggregation and generation of a hetero-oligomeric ring structure at the base of the infection cell is indispensable for plant infection. Furthermore, once the fungus enters host tissue it develops another infection structure, the transpressorium, enabling it to move between living host plant cells, which also requires septins for its function. Specific inhibition of septin aggregation—either genetically or with chemical inhibitors—prevents plant infection. Significantly, by screening for inhibitors of septin aggregation, broad spectrum anti-fungal compounds have been identified that prevent rice blast and a number of other cereal diseases in field trials. We review the recent advances in our understanding of septin biology and their potential as targets for crop disease control.

Widespread photosynthesis reaction centre barrel proteins are necessary for haloarchaeal cell division.

Cell division is fundamental to all cellular life. Most archaea depend on either the prokaryotic tubulin homologue FtsZ or the endosomal sorting complex required for transport for division but neither system has been robustly characterized. Here, we show that three of the four photosynthesis reaction centre barrel domain proteins of Haloferax volcanii (renamed cell division proteins B1/2/3 (CdpB1/2/3)) play important roles in cell division. CdpB1 interacts directly with the FtsZ membrane anchor SepF and is essential for cell division, whereas deletion of cdpB2 and cdpB3 causes a major and a minor division defect, respectively. Orthologues of CdpB proteins are also involved in cell division in other haloarchaea, indicating a conserved function of these proteins. Phylogenetic analysis shows that photosynthetic reaction centre barrel proteins are widely distributed among archaea and appear to be central to cell division in most if not all archaea.

The design of TOPK inhibitors using similarity search, molecular docking, and MD simulations

Cancer is still a major cause of death worldwide. Unfortunately, the majority of current anticancer treatments suffer many limitations, mainly emergence of resistance and lack of selectivity which necessitate the search for new therapeutics. The TOPK enzyme emerges as a promising target due to its overexpression in many cancer types while being rarely detected in normal tissues. Therefore, targeting TOPK would affect the malignant activity of cancerous cells while sparing normal ones. Further, its vital role in cell division, particularly in cytokinesis, adds to its safety to normal non-multiplying cells. In this study, a combined ligand and structure-based approach was utilized to identify potential TOPK inhibitors. Previously, we identified TOPK inhibitors using a structure-based approach following the construction of a 3D homology model of the TOPK enzyme. Herein, the most active identified inhibitor (lead) was used as a search query to conduct similarity search against PubChem and ChemBridge databases. Retrieved hits were filtered using drug-like filters, docked into the ATP binding site of the enzyme, and finally, the binding free energies of all docked poses were calculated. Based on the computational scores, eight hits were selected as potential TOPK inhibitors. The predicted ADMET descriptors of the eight selected hits were generally favorable. Further, MD simulations of the top scoring hit were conducted to investigate its binding dynamics compared to the lead compound and OTS964 which agreed with the docking results and propose the selected hits as potential TOPK inhibitors. Yet, biochemical testing is still needed to validate these results. Communicated by Ramaswamy H. Sarma

Microtubule-binding domains in Katanin p80 subunit are essential for severing activity in C. elegans.

Microtubule-severing enzymes (MSEs), such as Katanin, Spastin, and Fidgetin play essential roles in cell division and neurogenesis. They damage the microtubule (MT) lattice, which can either destroy or amplify the MT cytoskeleton, depending on the cellular context. However, little is known about how they interact with their substrates. We have identified the microtubule-binding domains (MTBD) required for Katanin function in C. elegans. Katanin is a heterohexamer of dimers containing a catalytic subunit p60 and a regulatory subunit p80, both of which are essential for female meiotic spindle assembly. Here, we report that p80-like(MEI-2) dictates Katanin binding to MTs via two MTBDs composed of basic patches. Substituting these patches reduces Katanin binding to MTs, compromising its function in female meiotic-spindle assembly. Structural alignments of p80-like(MEI-2) with p80s from different species revealed that the MTBDs are evolutionarily conserved, even if the specific amino acids involved vary. Our findings highlight the critical importance of the regulatory subunit (p80) in providing MT binding to the Katanin complex.