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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 -
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 -
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 -
DNA Repair Nov 2018Homologous recombination (HR) is a universally conserved mechanism used to maintain genomic integrity. In eukaryotes, HR is used to repair the spontaneous double strand... (Review)
Review
Homologous recombination (HR) is a universally conserved mechanism used to maintain genomic integrity. In eukaryotes, HR is used to repair the spontaneous double strand breaks (DSBs) that arise during mitotic growth, and the programmed DSBs that form during meiosis. The mechanisms that govern mitotic and meiotic HR share many similarities, however, there are also several key differences, which reflect the unique attributes of each process. For instance, even though many of the proteins involved in mitotic and meiotic HR are the same, DNA target specificity is not: mitotic DSBs are repaired primarily using the sister chromatid as a template, whereas meiotic DBSs are repaired primarily through targeting of the homologous chromosome. These changes in template specificity are induced by expression of meiosis-specific HR proteins, down-regulation of mitotic HR proteins, and the formation of meiosis-specific chromosomal structures. Here, we compare and contrast the biochemical properties of key recombination intermediates formed during the pre-synapsis phase of mitotic and meiotic HR. Throughout, we try to highlight unanswered questions that will shape our understanding of how homologous recombination contributes to human cancer biology and sexual reproduction.
Topics: Animals; Chromosome Pairing; Eukaryota; Homologous Recombination; Humans; Meiosis; Mitosis; Rad51 Recombinase
PubMed: 30195641
DOI: 10.1016/j.dnarep.2018.08.018 -
Stem Cell Research Oct 2017DMRT genes encode a deeply conserved family of transcription factors that share a unique DNA binding motif, the DM domain. DMRTs regulate development in a broad variety... (Review)
Review
DMRT genes encode a deeply conserved family of transcription factors that share a unique DNA binding motif, the DM domain. DMRTs regulate development in a broad variety of metazoans and they appear to have controlled sexual differentiation for hundreds of millions of years. In mice, starting during embryonic development, three Dmrt genes act sequentially to help establish and maintain spermatogenesis. Dmrt1 has notably diverse functions that include repressing pluripotency genes and promoting mitotic arrest in embryonic germ cells, reactivating prospermatogonia perinatally, establishing and maintaining spermatogonial stem cells (SSCs), promoting spermatogonial differentiation, and controlling the mitosis/meiosis switch. Dmrt6 acts in differentiating spermatogonia to coordinate an orderly exit from the mitotic/spermatogonial program and allow proper timing of entry to the meiotic/spermatocyte program. Finally, Dmrt7 takes over during the first meiotic prophase to help choreograph a transition in histone modifications that maintains transcriptional silencing of the sex chromosomes. The combined action of these three Dmrt genes helps ensure robust and sustainable spermatogenesis.
Topics: Animals; Cell Differentiation; Male; Mammals; Models, Biological; Spermatogenesis; Spermatozoa; Transcription Factors
PubMed: 28774758
DOI: 10.1016/j.scr.2017.07.026 -
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 -
Cellular Physiology and Biochemistry :... 2012Cytokinesis, the last major step of cell division, is a complex multistage process involving specific rearrangement of cellular cytoskeleton and a flurry of vesicular... (Review)
Review
Cytokinesis, the last major step of cell division, is a complex multistage process involving specific rearrangement of cellular cytoskeleton and a flurry of vesicular transport activities at the cell division plane. Vesicular traffic from the exocytic pathway and the endocytic/recycling pathway, operating again after being shut down since prophase, are engaged to supply the mitotic midzone with materials that would facilitate furrowing, midbody thinning and subsequent abscission of daughter cells. Cytokinesis is spatial and temporally regulated by mitotic kinases, and involves modulation by Arf and Rab small GTPases and their effectors. The latter include vesicle targeting and tethering molecules such as motor proteins, tethering complexes and SNAREs. The process of abscission requires the ultimate engagement of endosomal sorting complex required for transport (ESCRT) complexes. Although a good deal of details remains to be deciphered, cytokinesis in eukaryotes could essentially be visualized as a specialized cellular event requiring complex spatial and temporal regulated processes of membrane traffic.
Topics: Animals; Biological Transport; Cell Membrane; Cytokinesis; Humans; Membrane Proteins
PubMed: 23018421
DOI: 10.1159/000343301 -
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 -
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 -
Molecular Cancer Research : MCR Jan 2018To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and...
To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase C epsilon (PKCε) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase-anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCε in earlier (pre)mitotic events has not been addressed. Here, we now establish that PKCε controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKCε dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G checkpoint, a characteristic of many transformed cells. Thus, PKCε appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKCε as a potential cancer therapeutic target. The close relationship between PKCε dependency for mitotic spindle organization and the nonfunctionality of the TOPO2A-dependent G checkpoint, a hallmark of transformed cells, strongly suggests PKCε as a therapeutic target in cancer. .
Topics: Centrosome; Humans; M Phase Cell Cycle Checkpoints; Protein Kinase C-epsilon; Spindle Apparatus
PubMed: 29021232
DOI: 10.1158/1541-7786.MCR-17-0244