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Annual Review of Genetics Nov 2023The raison d'être of meiosis is shuffling of genetic information via Mendelian segregation and, within individual chromosomes, by DNA crossing-over. These outcomes are... (Review)
Review
The raison d'être of meiosis is shuffling of genetic information via Mendelian segregation and, within individual chromosomes, by DNA crossing-over. These outcomes are enabled by a complex cellular program in which interactions between homologous chromosomes play a central role. We first provide a background regarding the basic principles of this program. We then summarize the current understanding of the DNA events of recombination and of three processes that involve whole chromosomes: homolog pairing, crossover interference, and chiasma maturation. All of these processes are implemented by direct physical interaction of recombination complexes with underlying chromosome structures. Finally, we present convergent lines of evidence that the meiotic program may have evolved by coupling of this interaction to late-stage mitotic chromosome morphogenesis.
Topics: Chromosome Pairing; Meiosis; Chromosomes; DNA; Chromosome Segregation; Crossing Over, Genetic
PubMed: 37788458
DOI: 10.1146/annurev-genet-061323-044915 -
Royal Society Open Science Jun 2021Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved... (Review)
Review
Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.
PubMed: 34113447
DOI: 10.1098/rsos.201932 -
Annual Review of Plant Biology May 2022In contrast to well-studied fungal and animal cells, plant cells assemble bipolar spindles that exhibit a great deal of plasticity in the absence of structurally defined... (Review)
Review
In contrast to well-studied fungal and animal cells, plant cells assemble bipolar spindles that exhibit a great deal of plasticity in the absence of structurally defined microtubule-organizing centers like the centrosome. While plants employ some evolutionarily conserved proteins to regulate spindle morphogenesis and remodeling, many essential spindle assembly factors found in vertebrates are either missing or not required for producing the plant bipolar microtubule array. Plants also produce proteins distantly related to their fungal and animal counterparts to regulate critical events such as the spindle assembly checkpoint. Plant spindle assembly initiates with microtubule nucleation on the nuclear envelope followed by bipolarization into the prophase spindle. After nuclear envelope breakdown, kinetochore fibers are assembled and unified into the spindle apparatus with convergent poles. Of note, compared to fungal and animal systems, relatively little is known about how plant cells remodel the spindle microtubule array during anaphase. Uncovering mitotic functions of novel proteins for spindle assembly in plants will illuminate both common and divergent mechanisms employed by different eukaryotic organisms to segregate genetic materials.
Topics: Animals; Centrosome; Microtubules; Mitosis; Spindle Apparatus; Tubulin
PubMed: 35595291
DOI: 10.1146/annurev-arplant-070721-084258 -
Centrosome linker diversity and its function in centrosome clustering and mitotic spindle formation.The EMBO Journal Sep 2023The centrosome linker joins the two interphase centrosomes of a cell into one microtubule organizing center. Despite increasing knowledge on linker components, linker...
The centrosome linker joins the two interphase centrosomes of a cell into one microtubule organizing center. Despite increasing knowledge on linker components, linker diversity in different cell types and their role in cells with supernumerary centrosomes remained unexplored. Here, we identified Ninein as a C-Nap1-anchored centrosome linker component that provides linker function in RPE1 cells while in HCT116 and U2OS cells, Ninein and Rootletin link centrosomes together. In interphase, overamplified centrosomes use the linker for centrosome clustering, where Rootletin gains centrosome linker function in RPE1 cells. Surprisingly, in cells with centrosome overamplification, C-Nap1 loss prolongs metaphase through persistent activation of the spindle assembly checkpoint indicated by BUB1 and MAD1 accumulation at kinetochores. In cells lacking C-Nap1, the reduction of microtubule nucleation at centrosomes and the delay in nuclear envelop rupture in prophase probably cause mitotic defects like multipolar spindle formation and chromosome mis-segregation. These defects are enhanced when the kinesin HSET, which normally clusters multiple centrosomes in mitosis, is partially inhibited indicating a functional interplay between C-Nap1 and centrosome clustering in mitosis.
Topics: Centrosome; Cell Cycle; Cell Cycle Proteins; Interphase; Mitosis; Spindle Apparatus
PubMed: 37401899
DOI: 10.15252/embj.2021109738 -
Mathematical Biosciences May 2024This paper develops a theory for anaphase in cells. After a brief description of microtubules, the mitotic spindle and the centrosome, a mathematical model for anaphase...
This paper develops a theory for anaphase in cells. After a brief description of microtubules, the mitotic spindle and the centrosome, a mathematical model for anaphase is introduced and developed in the context of the cell cytoplasm and liquid crystalline structures. Prophase, prometaphase and metaphase are then briefly described in order to focus on anaphase, which is the main study of this paper. The entities involved are modelled in terms of liquid crystal defects and microtubules are represented as defect flux lines. The mathematical techniques employed make extensive use of energy considerations based on the work that was developed by Dafermos (1970) from the classical Frank-Oseen nematic liquid crystal energy (Frank, 1958; Oseen, 1933). With regard to liquid crystal theory we introduce the concept of regions of influence for defects which it is believed have important implications beyond the subject of this paper. The results of this paper align with observed biochemical phenomena and are explored in application to HeLa cells and Caenorhabditis elegans. This unified approach offers the possibility of gaining insight into various consequences of mitotic abnormalities which may result in Down syndrome, Hodgkin lymphoma, breast, prostate and various other types of cancer.
PubMed: 38795952
DOI: 10.1016/j.mbs.2024.109219 -
Biology of Reproduction Sep 2019Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. Most of our understanding of their functions has been obtained from studies in... (Review)
Review
Cyclins and cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. Most of our understanding of their functions has been obtained from studies in single-cell organisms and mitotically proliferating cultured cells. In mammals, there are more than 20 cyclins and 20 CDKs. Although genetic ablation studies in mice have shown that most of these factors are dispensable for viability and fertility, uncovering their functional redundancy, CCNA2, CCNB1, and CDK1 are essential for embryonic development. Cyclin/CDK complexes are known to regulate both mitotic and meiotic cell cycles. While some mechanisms are common to both types of cell divisions, meiosis has unique characteristics and requirements. During meiosis, DNA replication is followed by two successive rounds of cell division. In addition, mammalian germ cells experience a prolonged prophase I in males or a long period of arrest in prophase I in females. Therefore, cyclins and CDKs may have functions in meiosis distinct from their mitotic functions and indeed, meiosis-specific cyclins, CCNA1 and CCNB3, have been identified. Here, we describe recent advances in the field of cyclins and CDKs with a focus on meiosis and early embryogenesis.
Topics: Animals; Cyclin-Dependent Kinases; Cyclins; Embryo, Mammalian; Female; Gametogenesis; Germ Cells; Humans; Male; Mammals; Meiosis; Mice
PubMed: 31078132
DOI: 10.1093/biolre/ioz070 -
Cell Discovery May 2022Noncoding RNAs are known to associate with mitotic chromosomes, but the identities and functions of chromosome-associated RNAs in mitosis remain elusive. Here, we show...
Noncoding RNAs are known to associate with mitotic chromosomes, but the identities and functions of chromosome-associated RNAs in mitosis remain elusive. Here, we show that rRNA species associate with condensed chromosomes during mitosis. In particular, pre-rRNAs such as 45S, 32S, and 30S are highly enriched on mitotic chromosomes. Immediately following nucleolus disassembly in mitotic prophase, rRNAs are released and associate with and coat each condensed chromosome at prometaphase. Using unbiased mass spectrometry analysis, we further demonstrate that chromosome-bound rRNAs are associated with Ki-67. Moreover, the FHA domain and the repeat region of Ki-67 recognize and anchor rRNAs to chromosomes. Finally, suppression of chromosome-bound rRNAs by RNA polymerase I inhibition or by using rRNA-binding-deficient Ki-67 mutants impair mitotic chromosome dispersion during prometaphase. Our study thus reveals an important role of rRNAs in preventing chromosome clustering during mitosis.
PubMed: 35637200
DOI: 10.1038/s41421-022-00400-7 -
The Biochemical Journal Aug 2019The spatial configuration of chromatin is fundamental to ensure any given cell can fulfil its functional duties, from gene expression to specialised cellular division.... (Review)
Review
The spatial configuration of chromatin is fundamental to ensure any given cell can fulfil its functional duties, from gene expression to specialised cellular division. Significant technological innovations have facilitated further insights into the structure, function and regulation of three-dimensional chromatin organisation. To date, the vast majority of investigations into chromatin organisation have been conducted in interphase and mitotic cells leaving meiotic chromatin relatively unexplored. In combination, cytological and genome-wide contact frequency analyses in mammalian germ cells have recently demonstrated that large-scale chromatin structures in meiotic prophase I are reminiscent of the sequential loop arrays found in mitotic cells, although interphase-like segmentation of transcriptionally active and inactive regions are also evident along the length of chromosomes. Here, we discuss the similarities and differences of such large-scale chromatin architecture, between interphase, mitotic and meiotic cells, as well as their functional relevance and the proposed modulatory mechanisms which underlie them.
Topics: Animals; Chromatin; Germ Cells; Humans; Interphase; Meiosis; Mitosis
PubMed: 31383821
DOI: 10.1042/BCJ20180512 -
FEBS Letters Oct 2019The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical... (Review)
Review
The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical cell cycle-associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly, several CDKs exhibit meiosis-specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis-specific functions are mediated by both known CDK/cyclin complexes and meiosis-specific CDK-regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins, suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.
Topics: Animals; Cell Cycle Checkpoints; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinases; Cyclins; Gene Expression Regulation; Haploidy; Male; Meiosis; Mice; Nuclear Proteins; Recombination, Genetic; Signal Transduction; Spermatogenesis; Spermatozoa; Stem Cells
PubMed: 31566717
DOI: 10.1002/1873-3468.13627 -
Veterinary Pathology Mar 2021Counting mitotic figures (MF) in hematoxylin and eosin-stained histologic sections is an integral part of the diagnostic pathologist's tumor evaluation. The mitotic...
Counting mitotic figures (MF) in hematoxylin and eosin-stained histologic sections is an integral part of the diagnostic pathologist's tumor evaluation. The mitotic count (MC) is used alone or as part of a grading scheme for assessment of prognosis and clinical decisions. Determining MCs is subjective, somewhat laborious, and has interobserver variation. Proposals for standardizing this parameter in the veterinary field are limited to terminology (use of the term MC) and area (MC is counted in an area measuring 2.37 mm). Digital imaging techniques are now commonplace and widely used among veterinary pathologists, and field of view area can be easily calculated with digital imaging software. In addition to standardizing the methods of counting MF, the morphologic characteristics of MF and distinguishing atypical mitotic figures (AMF) versus mitotic-like figures (MLF) need to be defined. This article provides morphologic criteria for MF identification and for distinguishing normal phases of MF from AMF and MLF. Pertinent features of digital microscopy and application of computational pathology (CPATH) methods are discussed. Correct identification of MF will improve MC consistency, reproducibility, and accuracy obtained from manual (glass slide or whole-slide imaging) and CPATH approaches.
Topics: Animals; Eosine Yellowish-(YS); Hematoxylin; Mitotic Index; Reproducibility of Results; Software
PubMed: 33371818
DOI: 10.1177/0300985820980049