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Frontiers in Oncology 2015Aurora-A is a well-known mitotic kinase that regulates mitotic entry, spindle formation, and chromosome maturation as a canonical role. During mitosis, Aurora-A protein... (Review)
Review
Aurora-A is a well-known mitotic kinase that regulates mitotic entry, spindle formation, and chromosome maturation as a canonical role. During mitosis, Aurora-A protein is stabilized by its phosphorylation at Ser51 via blocking anaphase-promoting complex/cyclosome-mediated proteolysis. Importantly, overexpression and/or hyperactivation of Aurora-A is involved in tumorigenesis via aneuploidy and genomic instability. Recently, the novel function of Aurora-A for DNA replication has been revealed. In mammalian cells, DNA replication is strictly regulated for preventing over-replication. Pre-replication complex (pre-RC) formation is required for DNA replication as an initiation step occurring at the origin of replication. The timing of pre-RC formation depends on the protein level of geminin, which is controlled by the ubiquitin-proteasome pathway. Aurora-A phosphorylates geminin to prevent its ubiquitin-mediated proteolysis at the mitotic phase to ensure proper pre-RC formation and ensuing DNA replication. In this review, we introduce the novel non-canonical role of Aurora-A in DNA replication.
PubMed: 26380219
DOI: 10.3389/fonc.2015.00187 -
Nature Reviews. Molecular Cell Biology Feb 2015The appropriate timing of events that lead to chromosome segregation during mitosis and cytokinesis is essential to prevent aneuploidy, and defects in these processes... (Review)
Review
The appropriate timing of events that lead to chromosome segregation during mitosis and cytokinesis is essential to prevent aneuploidy, and defects in these processes can contribute to tumorigenesis. Key mitotic regulators are controlled through ubiquitylation and proteasome-mediated degradation. The APC/C (anaphase-promoting complex; also known as the cyclosome) is an E3 ubiquitin ligase that has a crucial function in the regulation of the mitotic cell cycle, particularly at the onset of anaphase and during mitotic exit. Co-activator proteins, inhibitor proteins, protein kinases and phosphatases interact with the APC/C to temporally and spatially control its activity and thus ensure accurate timing of mitotic events.
Topics: Anaphase-Promoting Complex-Cyclosome; Cell Cycle Proteins; Chromosome Segregation; Cytokinesis; Humans; Mitosis
PubMed: 25604195
DOI: 10.1038/nrm3934 -
Trends in Cell Biology Feb 2022The Chromosomal Passenger Complex (CPC) regulates a plethora of processes during multiple stages of nuclear and cytoplasmic division. Early during mitosis, the CPC is... (Review)
Review
The Chromosomal Passenger Complex (CPC) regulates a plethora of processes during multiple stages of nuclear and cytoplasmic division. Early during mitosis, the CPC is recruited to centromeres and kinetochores, and ensures that the duplicated chromosomes become properly connected to microtubules from opposite poles of the mitotic spindle. Progression into anaphase is accompanied by a striking relocation of the CPC from centromeres to the antiparallel microtubule overlaps of the anaphase spindle and to the equatorial cortex. This translocation requires direct interactions of the CPC with the kinesin-6 family member MKLP2/KIF20A, and the inactivation of cyclin B-cyclin-dependent kinase-1 (CDK1). Here, we review recent progress in the regulation of this relocation event. Furthermore, we discuss why the CPC must be relocated during early anaphase in light of recent advances in the functions of the CPC post metaphase.
Topics: Anaphase; Aurora Kinase B; Centromere; Chromosomal Proteins, Non-Histone; Humans; Microtubules; Mitosis; Spindle Apparatus
PubMed: 34663523
DOI: 10.1016/j.tcb.2021.09.008 -
Cell Cycle (Georgetown, Tex.) Oct 2021To ensure genome stability, chromosomes need to undergo proper condensation into two linked sister chromatids from prophase to prometaphase, followed by equal...
To ensure genome stability, chromosomes need to undergo proper condensation into two linked sister chromatids from prophase to prometaphase, followed by equal segregation at anaphase. Emerging evidence has shown that persistent DNA entanglements connecting the sister chromatids lead to the formation of ultrafine anaphase bridges (UFBs). If UFBs are not resolved soon after anaphase, they can induce chromosome missegregation. PICH (PLK1-interacting checkpoint helicase) is a DNA translocase that localizes on chromosome arms, centromeres and UFBs. It plays multiple essential roles in mitotic chromosome organization and segregation. PICH also recruits other associated proteins to UFBs, and together they mediate UFB resolution. Here, the proposed mechanism behind PICH's functions in chromosome organization and UFB resolution will be discussed. We summarize the regulation of PICH action at chromosome arms and centromeres, how PICH recognizes UFBs and recruits other UFB-associated factors, and finally how PICH promotes UFB resolution together with other DNA processing enzymes.
Topics: Anaphase; Centromere; Chromatids; Chromosome Segregation; Genomic Instability; Humans; Mitosis
PubMed: 34530686
DOI: 10.1080/15384101.2021.1970877 -
Genes Jan 2022Oligo-fluorescence in situ hybridization (FISH) facilitates precise chromosome identification and comparative cytogenetic analysis. Detection of autosomal chromosomes of...
Oligo-fluorescence in situ hybridization (FISH) facilitates precise chromosome identification and comparative cytogenetic analysis. Detection of autosomal chromosomes of has not been achieved using oligonucleotide sequences. Here, the chromosomes of five taxa in the mitotic metaphase and mitotic metaphase to anaphase were detected using the oligo-FISH probes (AGT), 5S rDNA, and (TTG). In total, 24 small chromosomes were clearly observed in the mitotic metaphase (0.89-3.03 μm), whereas 24-48 small chromosomes were observed in the mitotic metaphase to anaphase (0.94-3.10 μm). The signal number and intensity of (AGT), 5S rDNA, and (TTG) in the mitotic metaphase to anaphase chromosomes were nearly consistent with those in the mitotic metaphase chromosomes when the two split chromosomes were integrated as one unit. Of note, 14 chromosomes (there is a high chance that sex chromosomes are included) were exclusively identified by (AGT), 5S rDNA, and (TTG). The other 10 also showed a terminal signal with (AGT). Moreover, these oligo-probes were able to distinguish one wild taxon from four taxa. These chromosome identification and taxa differentiation data will help in elucidating visual and elaborate physical mapping and guide breeders' utilization of wild resources of .
Topics: Chromosomes, Plant; DNA, Ribosomal; Hippophae; In Situ Hybridization, Fluorescence; RNA, Ribosomal, 5S
PubMed: 35205242
DOI: 10.3390/genes13020195 -
Nature Jun 2020During cell division, remodelling of the nuclear envelope enables chromosome segregation by the mitotic spindle. The reformation of sealed nuclei requires ESCRTs...
During cell division, remodelling of the nuclear envelope enables chromosome segregation by the mitotic spindle. The reformation of sealed nuclei requires ESCRTs (endosomal sorting complexes required for transport) and LEM2, a transmembrane ESCRT adaptor. Here we show how the ability of LEM2 to condense on microtubules governs the activation of ESCRTs and coordinated spindle disassembly. The LEM motif of LEM2 binds BAF, conferring on LEM2 an affinity for chromatin, while an adjacent low-complexity domain (LCD) promotes LEM2 phase separation. A proline-arginine-rich sequence within the LCD binds to microtubules and targets condensation of LEM2 to spindle microtubules that traverse the nascent nuclear envelope. Furthermore, the winged-helix domain of LEM2 activates the ESCRT-II/ESCRT-III hybrid protein CHMP7 to form co-oligomeric rings. Disruption of these events in human cells prevented the recruitment of downstream ESCRTs, compromised spindle disassembly, and led to defects in nuclear integrity and DNA damage. We propose that during nuclear reassembly LEM2 condenses into a liquid-like phase and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin and the spindle. The properties of LEM2 described here, and the homologous architectures of related inner nuclear membrane proteins, suggest that phase separation may contribute to other critical envelope functions, including interphase repair and chromatin organization.
Topics: Anaphase; Chromatin; DNA Damage; DNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport; HeLa Cells; Humans; Membrane Proteins; Microtubules; Nuclear Envelope; Nuclear Proteins; Spindle Apparatus
PubMed: 32494070
DOI: 10.1038/s41586-020-2232-x -
Frontiers in Genetics 2022To sustain genomic stability by correct DNA replication and mitosis, cell cycle progression is tightly controlled by the cyclic activity of cyclin-dependent kinases,... (Review)
Review
To sustain genomic stability by correct DNA replication and mitosis, cell cycle progression is tightly controlled by the cyclic activity of cyclin-dependent kinases, their binding to cyclins in the respective phase and the regulation of cyclin levels by ubiquitin-dependent proteolysis. The spindle assembly checkpoint plays an important role at the metaphase-anaphase transition to ensure a correct separation of sister chromatids before cytokinesis and to initiate mitotic exit, as an incorrect chromosome distribution may lead to genetically unstable cells and tumorigenesis. The ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C) is essential for these processes by mediating the proteasomal destruction of cyclins and other important cell cycle regulators. To this end, it interacts with the two regulatory subunits Cdh1 and Cdc20. Both play a role in tumorigenesis with Cdh1 being a tumor suppressor and Cdc20 an oncogene. In this review, we summarize the current knowledge about the APC/C-regulators Cdh1 and Cdc20 in tumorigenesis and potential targeted therapeutic approaches.
PubMed: 35832196
DOI: 10.3389/fgene.2022.941565 -
Seminars in Cancer Biology Dec 2020The anaphase promoting complex/ cyclosome (APC/C), is an evolutionarily conserved protein complex essential for cellular division due to its role in regulating the... (Review)
Review
The anaphase promoting complex/ cyclosome (APC/C), is an evolutionarily conserved protein complex essential for cellular division due to its role in regulating the mitotic transition from metaphase to anaphase. In this review, we highlight recent work that has shed light on our understanding of the role of APC/C coactivators, Cdh1 and Cdc20, in cancer initiation and development. We summarize the current state of knowledge regarding APC/C structure and function, as well as the distinct ways Cdh1 and Cdc20 are dysregulated in human cancer. We also discuss APC/C inhibitors, novel approaches for targeting the APC/C as a cancer therapy, and areas for future work.
Topics: Anaphase-Promoting Complex-Cyclosome; Antigens, CD; Antineoplastic Agents; Carbamates; Cdc20 Proteins; Cdh1 Proteins; Diamines; Genomic Instability; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 32165320
DOI: 10.1016/j.semcancer.2020.03.001 -
Cytoskeleton (Hoboken, N.J.) 2023Accurate placement of the cleavage furrow is crucial for successful cell division. Recent advancements have revealed that diverse mechanisms have evolved across...
Accurate placement of the cleavage furrow is crucial for successful cell division. Recent advancements have revealed that diverse mechanisms have evolved across different branches of the phylogenetic tree. Here, we employed Dictyostelium cells to validate previous models. We observed that during metaphase and early anaphase, mitotic spindles exhibited random rotary movements which ceased when the spindle elongated by approximately 7 μm. At this point, astral microtubules reached the polar cell cortex and fixed the spindle axis, causing cells to elongate by extending polar pseudopods and divide along the spindle axis. Therefore, the position of the furrow is determined when the spindle orientation is fixed. The distal ends of astral microtubules stimulate the extension of pseudopods at the polar cortex. One signal for pseudopod extension may be phosphatidylinositol trisphosphate in the cell membrane, but there appears to be another unknown signal. At the onset of polar pseudopod extension, cortical flow began from both poles toward the equator. We suggest that polar stimulation by astral microtubules determines the furrow position, induces polar pseudopod extension and cortical flow, and accumulates the elements necessary for the construction of the contractile ring.
Topics: Dictyostelium; Phylogeny; Cytokinesis; Microtubules; Spindle Apparatus; Anaphase
PubMed: 37650534
DOI: 10.1002/cm.21784 -
FEBS Letters Oct 2019Here, we will review the evidence showing that mitotic exit is initiated by regulated proteolysis and then driven by the PPP family of phosphoserine/threonine... (Review)
Review
Here, we will review the evidence showing that mitotic exit is initiated by regulated proteolysis and then driven by the PPP family of phosphoserine/threonine phosphatases. Rapid APC/C and ubiquitin-dependent proteolysis of cyclin B and securin initiates sister chromatid separation, the first step of mitotic exit. Because proteolysis of Aurora and Polo family kinases dependent on APC/C is relatively slow, this creates a new regulatory state, anaphase, different to G2 and M-phase. We will discuss how the CDK1-counteracting phosphatases PP1 and PP2A-B55, together with Aurora and Polo kinases, contribute to the temporal regulation and order of events in the different stages of mitotic exit from anaphase to cytokinesis. For PP2A-B55, these timing properties are created by the ENSA-dependent inhibitory pathway and differential recognition of phosphoserine and phosphothreonine. Finally, we will discuss how Aurora B and PP2A-B56 are needed for the spatial regulation of anaphase spindle formation and how APC/C-dependent destruction of PLK1 acts as a timer for abscission, the final event of cytokinesis.
Topics: Anaphase-Promoting Complex-Cyclosome; Antigens, CD; Aurora Kinase A; Cadherins; Cdc20 Proteins; Cell Cycle Proteins; Cyclin B; Cytokinesis; Gene Expression Regulation; Humans; M Phase Cell Cycle Checkpoints; Protein Phosphatase 1; Protein Phosphatase 2; Protein Serine-Threonine Kinases; Proteolysis; Proto-Oncogene Proteins; Securin; Signal Transduction; Spatio-Temporal Analysis; Polo-Like Kinase 1
PubMed: 31494926
DOI: 10.1002/1873-3468.13595