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Bulletin Du Cancer Oct 2011Genomic DNA is constantly under stress of endogenous and exogenous DNA damaging agents. Without proper care, the DNA damage causes an alteration of the genomic structure... (Review)
Review
Genomic DNA is constantly under stress of endogenous and exogenous DNA damaging agents. Without proper care, the DNA damage causes an alteration of the genomic structure and can lead to cell death or the occurrence of mutations involved in tumorigenesis. During the process of evolution, organisms have acquired a series of response mechanisms and repair of DNA damage, thereby ensuring the maintenance of genome stability and faithful transmission of genetic information. The checkpoints are the major mechanisms by which a cell can respond to DNA damage, either by actively stopping the cell cycle or by induction of apoptosis. Two parallel signalling pathways, ATM and ATR respond to genotoxic stress by activating their downstream target proteins including the two effectors kinases CHK1 and CHK2. Promising preliminary data render these proteins potential targets for therapeutic development against cancer.
Topics: Aneuploidy; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Cycle; Cell Cycle Proteins; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Damage; DNA Repair; DNA-Binding Proteins; Enzyme Activation; Genomic Instability; Humans; Interphase; Mitosis; Molecular Targeted Therapy; Neoplasms; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; Tumor Suppressor Proteins
PubMed: 21669563
DOI: 10.1684/bdc.2011.1382 -
Journal of Cell Science Sep 2020Human retinal pigment epithelial-1 (RPE-1) cells are increasingly being used as a model to study mitosis because they represent a non-transformed alternative to cancer...
Human retinal pigment epithelial-1 (RPE-1) cells are increasingly being used as a model to study mitosis because they represent a non-transformed alternative to cancer cell lines, such as HeLa cervical adenocarcinoma cells. However, the lack of an efficient method to synchronize RPE-1 cells in mitosis precludes their application for large-scale biochemical and proteomics assays. Here, we report a protocol to synchronize RPE-1 cells based on sequential treatments with the Cdk4 and Cdk6 inhibitor PD 0332991 (palbociclib) and the microtubule-depolymerizing drug nocodazole. With this method, the vast majority (80-90%) of RPE-1 cells arrested at prometaphase and exited mitosis synchronously after release from nocodazole. Moreover, the cells fully recovered and re-entered the cell cycle after the palbociclib-nocodazole block. Finally, we show that this protocol could be successfully employed for the characterization of the protein-protein interaction network of the kinetochore protein Ndc80 by immunoprecipitation coupled with mass spectrometry. This synchronization method significantly expands the versatility and applicability of RPE-1 cells to the study of cell division and might be applied to other cell lines that do not respond to treatments with DNA synthesis inhibitors.
Topics: Humans; Kinetochores; Mitosis; Nocodazole; Prometaphase; Retinal Pigments
PubMed: 32878943
DOI: 10.1242/jcs.247940 -
Biomolecules Feb 2019Mitosis requires extensive rearrangement of cellular architecture and of subcellular structures so that replicated chromosomes can bind correctly to spindle microtubules... (Review)
Review
Mitosis requires extensive rearrangement of cellular architecture and of subcellular structures so that replicated chromosomes can bind correctly to spindle microtubules and segregate towards opposite poles. This process originates two new daughter nuclei with equal genetic content and relies on highly-dynamic and tightly regulated phosphorylation of numerous cell cycle proteins. A burst in protein phosphorylation orchestrated by several conserved kinases occurs as cells go into and progress through mitosis. The opposing dephosphorylation events are catalyzed by a small set of protein phosphatases, whose importance for the accuracy of mitosis is becoming increasingly appreciated. This review will focus on the established and emerging roles of mitotic phosphatases, describe their structural and biochemical properties, and discuss recent advances in understanding the regulation of phosphatase activity and function.
Topics: Animals; Humans; Mitosis; Phosphoric Monoester Hydrolases; Phosphorylation
PubMed: 30736436
DOI: 10.3390/biom9020055 -
Molecular Cell May 2023Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al. reveal that glycolysis...
Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al. reveal that glycolysis end-product lactate directly binds and inhibits the SUMO protease SENP1 to govern the E3 ligase activity of the anaphase-promoting complex, leading to efficient mitotic exit in proliferative cells.
Topics: Anaphase; Lactic Acid; Mitosis; Anaphase-Promoting Complex-Cyclosome; Cell Cycle Proteins
PubMed: 37207623
DOI: 10.1016/j.molcel.2023.04.013 -
International Journal of Molecular... Aug 2017Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in... (Review)
Review
Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.
Topics: Animals; Autophagy; Humans; Mitosis; Protein Kinases
PubMed: 28858266
DOI: 10.3390/ijms18091884 -
Biochemical Pharmacology Aug 2021Dysregulation of cell cycle progression is a hallmark of cancer cells. In recent years, efforts have been devoted to the development of new therapies that target... (Review)
Review
Dysregulation of cell cycle progression is a hallmark of cancer cells. In recent years, efforts have been devoted to the development of new therapies that target proteins involved in cell cycle regulation and mitosis. Novel targeted antimitotic drugs include inhibitors of aurora kinase family, polo-like kinase 1, Mps1, Eg5, CENP-5 and the APC/cyclosome complex. While certain new inhibitors reached the clinical trial stage, most were discontinued due to negative results. However, these therapies should not be readily dismissed. Based on recent advances concerning their mechanisms of action, new strategies could be devised to increase their efficacy and promote further clinical trials. Here we discuss three main lines of action to empower these therapeutic approaches: increasing cell death signals during mitotic arrest, targeting senescent cells and facilitating antitumor immune response through immunogenic cell death (ICD).
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Mitosis; Neoplasms
PubMed: 34129859
DOI: 10.1016/j.bcp.2021.114655 -
Cells Apr 2022A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association... (Review)
Review
A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association between pericentric heterochromatin and the centromere is essential for proper metaphase exit and progression into telophase. Analysis of chromosome rearrangements that separate pericentric heterochromatin and centromeres indicates that they must remain associated in order to balance Cohesin/DNA catenation-based binding forces and centromere-based pulling forces during the metaphase-anaphase transition. In addition, a centromere embedded in heterochromatin facilitates nuclear envelope assembly around the entire complement of segregating chromosomes. Because the nuclear envelope initially forms on pericentric heterochromatin, nuclear envelope formation proceeds from the pole, thus providing time for incorporation of lagging and trailing chromosome arms into the newly formed nucleus. Additional analysis of noncanonical mitoses provides further insights into the functional significance of the tight association between heterochromatin and centromeres.
Topics: Anaphase; Centromere; Heterochromatin; Metaphase; Mitosis
PubMed: 35406810
DOI: 10.3390/cells11071247 -
Biochemical Pharmacology Sep 2019Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the... (Review)
Review
Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the metaphase plate, chromosome segregation and cytokinesis. Poly(ADP-ribose) polymerases (PARPs), in particular PARP1, PARP2, PARP3, PARP5a (TNKS1), as well as poly(ADP-ribose) glycohydrolase (PARG), regulate different mitotic functions, including centrosome function, mitotic spindle assembly, mitotic checkpoints, telomere length and telomere cohesion. PARP depletion or inhibition give rise to various mitotic defects such as centrosome amplification, multipolar spindles, chromosome misalignment, premature loss of cohesion, metaphase arrest, anaphase DNA bridges, lagging chromosomes, and micronuclei. As the mechanisms of PARP1/2 inhibitor-mediated cell death are being progressively elucidated, it is becoming clear that mitotic defects caused by PARP1/2 inhibition arise due to replication stress and DNA damage in S phase. As it stands, entrapment of inactive PARP1/2 on DNA phenocopies replication stress through accumulation of unresolved replication intermediates, double-stranded DNA breaks (DSBs) and incorrectly repaired DSBs, which can be transmitted from S phase to mitosis and instigate various mitotic defects, giving rise to both numerical and structural chromosomal aberrations. Cancer cells have increased levels of replication stress, which makes them particularly susceptible to a combination of agents that compromise replication fork stability. Indeed, combining PARP1/2 inhibitors with genetic deficiencies in DNA repair pathways, DNA-damaging agents, ATR and other cell cycle checkpoint inhibitors has yielded synergistic effects in killing cancer cells. Here I provide a comprehensive overview of the mitotic functions of PARPs and PARG, mitotic phenotypes induced by their depletion or inhibition, as well as the therapeutic relevance of targeting mitotic cells by directly interfering with mitotic functions or indirectly through replication stress.
Topics: Animals; DNA Damage; DNA Repair; Humans; Mitosis; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 30910692
DOI: 10.1016/j.bcp.2019.03.028 -
Quarterly Reviews of Biophysics May 2012Mitosis is the process by which eukaryotic cells organize and segregate their chromosomes in preparation for cell division. It is accomplished by a cellular machine... (Review)
Review
Mitosis is the process by which eukaryotic cells organize and segregate their chromosomes in preparation for cell division. It is accomplished by a cellular machine composed largely of microtubules (MTs) and their associated proteins. This article reviews literature on mitosis from a biophysical point of view, drawing attention to the assembly and motility processes required to do this complex job with precision. Work from both the recent and the older literature is integrated into a description of relevant biological events and the experiments that probe their mechanisms. Theoretical work on specific subprocesses is also reviewed. Our goal is to provide a document that will expose biophysicists to the fascination of this quite amazing process and provide them with a good background from which they can pursue their own research interests in the subject.
Topics: Biophysical Phenomena; Humans; Mitosis; Models, Biological
PubMed: 22321376
DOI: 10.1017/S0033583512000017 -
Seminars in Cancer Biology Jan 2023The nucleus undergoes dramatic structural and functional changes during cell division. With the entry into mitosis, in human cells the nuclear envelope breaks down,... (Review)
Review
The nucleus undergoes dramatic structural and functional changes during cell division. With the entry into mitosis, in human cells the nuclear envelope breaks down, chromosomes rearrange into rod-like structures which are collected and segregated by the spindle apparatus. While these processes in the first half of mitosis have been intensively studied, much less is known about the second half of mitosis, when a functional nucleus reforms in each of the emerging cells. Here we review our current understanding of mitotic exit and nuclear reformation with spotlights on the links to cancer biology.
Topics: Humans; Neoplasms; Mitosis; Cell Nucleus; Chromosomes; Biology
PubMed: 36436712
DOI: 10.1016/j.semcancer.2022.11.013