Regulation of Mitotic Exit by Cell Cycle Checkpoints: Lessons from Saccharomyces Cerevisiae
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Meiotic Prophase Abnormalities and Metaphase Cell Death in MLH1-Deficient Mouse Spermatocytes: Insights Into Regulation of Spermatogenic Progress
Developmental Biology 249, 85–95 (2002) doi:10.1006/dbio.2002.0708 Meiotic Prophase Abnormalities and Metaphase Cell Death in MLH1-Deficient Mouse Spermatocytes: Insights into Regulation of Spermatogenic Progress Shannon Eaker,1 John Cobb,2 April Pyle, and Mary Ann Handel3 Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996 The MLH1 protein is required for normal meiosis in mice and its absence leads to failure in maintenance of pairing between bivalent chromosomes, abnormal meiotic division, and ensuing sterility in both sexes. In this study, we investigated whether failure to develop foci of MLH1 protein on chromosomes in prophase would lead to elimination of prophase spermatocytes, and, if not, whether univalent chromosomes could align normally on the meiotic spindle and whether metaphase spermatocytes would be delayed and/or eliminated. In spite of the absence of MLH1 foci, no apoptosis of spermatocytes in prophase was detected. In fact, chromosomes of pachytene spermatocytes from Mlh1؊/؊ mice were competent to condense metaphase chromosomes, both in vivo and in vitro. Most condensed chromosomes were univalents with spatially distinct FISH signals. Typical metaphase events, such as synaptonemal complex breakdown and the phosphorylation of Ser10 on histone H3, occurred in Mlh1؊/؊ spermatocytes, suggesting that there is no inhibition of onset of meiotic metaphase in the face of massive chromosomal abnormalities. However, the condensed univalent chromosomes did not align correctly onto the spindle apparatus in the majority of Mlh1؊/؊ spermatocytes. Most meiotic metaphase spermatocytes were characterized with bipolar spindles, but chromosomes radiated away from the microtubule-organizing centers in a prometaphase-like pattern rather than achieving a bipolar orientation. -
Meiotic Cohesin and Variants Associated with Human Reproductive Aging and Disease
fcell-09-710033 July 27, 2021 Time: 16:27 # 1 REVIEW published: 02 August 2021 doi: 10.3389/fcell.2021.710033 Meiotic Cohesin and Variants Associated With Human Reproductive Aging and Disease Rachel Beverley1, Meredith L. Snook1 and Miguel Angel Brieño-Enríquez2* 1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States, 2 Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States Successful human reproduction relies on the well-orchestrated development of competent gametes through the process of meiosis. The loading of cohesin, a multi- protein complex, is a key event in the initiation of mammalian meiosis. Establishment of sister chromatid cohesion via cohesin rings is essential for ensuring homologous recombination-mediated DNA repair and future proper chromosome segregation. Cohesin proteins loaded during female fetal life are not replenished over time, and therefore are a potential etiology of age-related aneuploidy in oocytes resulting in Edited by: decreased fecundity and increased infertility and miscarriage rates with advancing Karen Schindler, Rutgers, The State University maternal age. Herein, we provide a brief overview of meiotic cohesin and summarize of New Jersey, United States the human genetic studies which have identified genetic variants of cohesin proteins and Reviewed by: the associated reproductive phenotypes -
DNA Damage Checkpoint Dynamics Drive Cell Cycle Phase Transitions
bioRxiv preprint doi: https://doi.org/10.1101/137307; this version posted August 4, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. DNA damage checkpoint dynamics drive cell cycle phase transitions Hui Xiao Chao1,2, Cere E. Poovey1, Ashley A. Privette1, Gavin D. Grant3,4, Hui Yan Chao1, Jeanette G. Cook3,4, and Jeremy E. Purvis1,2,4,† 1Department of Genetics 2Curriculum for Bioinformatics and Computational Biology 3Department of Biochemistry and Biophysics 4Lineberger Comprehensive Cancer Center University of North Carolina, Chapel Hill 120 Mason Farm Road Chapel Hill, NC 27599-7264 †Corresponding Author: Jeremy Purvis Genetic Medicine Building 5061, CB#7264 120 Mason Farm Road Chapel Hill, NC 27599-7264 [email protected] ABSTRACT DNA damage checkpoints are cellular mechanisms that protect the integrity of the genome during cell cycle progression. In response to genotoxic stress, these checkpoints halt cell cycle progression until the damage is repaired, allowing cells enough time to recover from damage before resuming normal proliferation. Here, we investigate the temporal dynamics of DNA damage checkpoints in individual proliferating cells by observing cell cycle phase transitions following acute DNA damage. We find that in gap phases (G1 and G2), DNA damage triggers an abrupt halt to cell cycle progression in which the duration of arrest correlates with the severity of damage. However, cells that have already progressed beyond a proposed “commitment point” within a given cell cycle phase readily transition to the next phase, revealing a relaxation of checkpoint stringency during later stages of certain cell cycle phases. -
Distinct Functions of Human Cohesin-SA1 and Cohesin-SA2 in Double-Strand Break Repair
Distinct Functions of Human Cohesin-SA1 and Cohesin-SA2 in Double-Strand Break Repair Xiangduo Kong,a Alexander R. Ball, Jr.,a Hoang Xuan Pham,a Weihua Zeng,a* Hsiao-Yuan Chen,a John A. Schmiesing,a Jong-Soo Kim,a* Michael Berns,b,c Kyoko Yokomoria Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USAa; Beckman Laser Instituteb and Department of Biomedical Engineering, Samueli School of Engineering,c University of California, Irvine, California, USA Cohesin is an essential multiprotein complex that mediates sister chromatid cohesion critical for proper segregation of chromo- somes during cell division. Cohesin is also involved in DNA double-strand break (DSB) repair. In mammalian cells, cohesin is involved in both DSB repair and the damage checkpoint response, although the relationship between these two functions is un- clear. Two cohesins differing by one subunit (SA1 or SA2) are present in somatic cells, but their functional specificities with re- gard to DNA repair remain enigmatic. We found that cohesin-SA2 is the main complex corecruited with the cohesin-loading factor NIPBL to DNA damage sites in an S/G2-phase-specific manner. Replacing the diverged C-terminal region of SA1 with the corresponding region of SA2 confers this activity on SA1. Depletion of SA2 but not SA1 decreased sister chromatid homologous recombination repair and affected repair pathway choice, indicating that DNA repair activity is specifically associated with cohe- sin recruited to damage sites. In contrast, both cohesin complexes function in the intra-S checkpoint, indicating that cell cycle- specific damage site accumulation is not a prerequisite for cohesin’s intra-S checkpoint function. -
Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its
Published OnlineFirst January 21, 2015; DOI: 10.1158/1078-0432.CCR-14-1950 Biology of Human Tumors Clinical Cancer Research Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis Longlong Cao1,2, Jiechao Zhou2, Junrong Zhang1,2, Sijin Wu3, Xintao Yang1,2, Xin Zhao2, Huifang Li2, Ming Luo1, Qian Yu1, Guangtan Lin1, Huizhong Lin1, Jianwei Xie1, Ping Li1, Xiaoqing Hu3, Chaohui Zheng1, Guojun Bu2, Yun-wu Zhang2,4, Huaxi Xu2,4,5, Yongliang Yang3, Changming Huang1, and Jie Zhang2,4 Abstract Purpose: As a cyclin-independent atypical CDK, the role of correlated with the severity of gastric cancer based on tumor CDK5 in regulating cell proliferation in gastric cancer remains and lymph node metastasis and patient 5-year fatality rate. unknown. Nuclear localization of CDK5 was found to be significantly Experimental Design: Expression of CDK5 in gastric tumor decreased in tumor tissues and gastric cancer cell lines, and paired adjacent noncancerous tissues from 437 patients was whereas exogenously expression of nucleus-targeted CDK5 measured by Western blotting, immunohistochemistry, and real- inhibited the proliferation and xenograft implantation of time PCR. The subcellular translocation of CDK5 was monitored gastric cancer cells. Treatment with the small molecule during gastric cancer cell proliferation. The role of nuclear CDK5 NS-0011, which increases CDK5 accumulation in the nucleus, in gastric cancer tumorigenic proliferation and ex vivo xenografts suppressed both cancer cell proliferation and xenograft was explored. Furthermore, by screening for compounds in the tumorigenesis. PubChem database that disrupt CDK5 association with its nu- Conclusions: Our results suggest that low CDK5 expression is clear export facilitator, we identified a small molecular (NS-0011) associated with poor overall survival in patients with gastric that inhibits gastric cancer cell growth. -
Prospects & Overviews Meiotic Versus Mitotic Recombination: Two Different
Prospects & Overviews Meiotic versus mitotic recombination: Two different routes for double-strand Review essays break repair The different functions of meiotic versus mitotic DSB repair are reflected in different pathway usage and different outcomes Sabrina L. Andersen1) and Jeff Sekelsky1)2)Ã Studies in the yeast Saccharomyces cerevisiae have vali- Introduction dated the major features of the double-strand break repair (DSBR) model as an accurate representation of The existence of DNA recombination was revealed by the behavior of segregating traits long before DNA was identified the pathway through which meiotic crossovers (COs) are as the bearer of genetic information. At the start of the 20th produced. This success has led to this model being century, pioneering Drosophila geneticists studied the behav- invoked to explain double-strand break (DSB) repair in ior of chromosomal ‘‘factors’’ that determined traits such as other contexts. However, most non-crossover (NCO) eye color, wing shape, and bristle length. In 1910 Thomas Hunt recombinants generated during S. cerevisiae meiosis do Morgan published the observation that the linkage relation- not arise via a DSBR pathway. Furthermore, it is becom- ships of these factors were shuffled during meiosis [1]. Building on this discovery, in 1913 A. H. Sturtevant used ing increasingly clear that DSBR is a minor pathway for linkage analysis to determine the order of factors (genes) recombinational repair of DSBs that occur in mitotically- on a chromosome, thus simultaneously establishing that proliferating cells and that the synthesis-dependent genes are located at discrete physical locations along chromo- strand annealing (SDSA) model appears to describe somes as well as originating the classic tool of genetic map- mitotic DSB repair more accurately. -
Investigating the Role of Cdk11in Animal Cytokinesis
Investigating the Role of CDK11 in Animal Cytokinesis by Thomas Clifford Panagiotou A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Molecular Genetics University of Toronto © Copyright by Thomas Clifford Panagiotou (2020) Investigating the Role of CDK11 in Animal Cytokinesis Thomas Clifford Panagiotou Master of Science Department of Molecular Genetics University of Toronto 2020 Abstract Finely tuned spatio-temporal regulation of cell division is required for genome stability. Cytokinesis constitutes the final stages of cell division, from chromosome segregation to the physical separation of cells, abscission. Abscission is tightly regulated to ensure it occurs after earlier cytokinetic events, like the maturation of the stem body, the regulatory platform for abscission. Active Aurora B kinase enforces the abscission checkpoint, which blocks abscission until chromosomes have been cleared from the cytokinetic machinery. Currently, it is unclear how this checkpoint is overcome. Here, I demonstrate that the cyclin-dependent kinase CDK11 is required for cytokinesis. Both inhibition and depletion of CDK11 block abscission. Furthermore, the mitosis-specific CDK11p58 kinase localizes to the stem body, where its kinase activity rescues the defects of CDK11 depletion and inhibition. These results suggest a model whereby CDK11p58 antagonizes Aurora B kinase to overcome the abscission checkpoint to allow for successful completion of cytokinesis. ii Acknowledgments I am very grateful for the support of my family and friends throughout my studies. I would also like to express my deep gratitude to Wilde Lab members, both past and present, for their advice and collaboration. In particular, I am very grateful to Matthew Renshaw, whose work comprises part of this thesis. -
Mitosis Vs. Meiosis
Mitosis vs. Meiosis In order for organisms to continue growing and/or replace cells that are dead or beyond repair, cells must replicate, or make identical copies of themselves. In order to do this and maintain the proper number of chromosomes, the cells of eukaryotes must undergo mitosis to divide up their DNA. The dividing of the DNA ensures that both the “old” cell (parent cell) and the “new” cells (daughter cells) have the same genetic makeup and both will be diploid, or containing the same number of chromosomes as the parent cell. For reproduction of an organism to occur, the original parent cell will undergo Meiosis to create 4 new daughter cells with a slightly different genetic makeup in order to ensure genetic diversity when fertilization occurs. The four daughter cells will be haploid, or containing half the number of chromosomes as the parent cell. The difference between the two processes is that mitosis occurs in non-reproductive cells, or somatic cells, and meiosis occurs in the cells that participate in sexual reproduction, or germ cells. The Somatic Cell Cycle (Mitosis) The somatic cell cycle consists of 3 phases: interphase, m phase, and cytokinesis. 1. Interphase: Interphase is considered the non-dividing phase of the cell cycle. It is not a part of the actual process of mitosis, but it readies the cell for mitosis. It is made up of 3 sub-phases: • G1 Phase: In G1, the cell is growing. In most organisms, the majority of the cell’s life span is spent in G1. • S Phase: In each human somatic cell, there are 23 pairs of chromosomes; one chromosome comes from the mother and one comes from the father. -
Cohesin Architecture and Clustering in Vivo Siheng Xiang, Douglas Koshland*
RESEARCH ARTICLE Cohesin architecture and clustering in vivo Siheng Xiang, Douglas Koshland* Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States Abstract Cohesin helps mediate sister chromatid cohesion, chromosome condensation, DNA repair, and transcription regulation. We exploited proximity-dependent labeling to define the in vivo interactions of cohesin domains with DNA or with other cohesin domains that lie within the same or in different cohesin complexes. Our results suggest that both cohesin’s head and hinge domains are proximal to DNA, and cohesin structure is dynamic with differential folding of its coiled coil regions to generate butterfly confirmations. This method also reveals that cohesins form ordered clusters on and off DNA. The levels of cohesin clusters and their distribution on chromosomes are cell cycle-regulated. Cohesin clustering is likely necessary for cohesion maintenance because clustering and maintenance uniquely require the same subset of cohesin domains and the auxiliary cohesin factor Pds5p. These conclusions provide important new mechanistic and biological insights into the architecture of the cohesin complex, cohesin–cohesin interactions, and cohesin’s tethering and loop-extruding activities. Introduction Chromosome segregation, DNA damage repair, and the regulation of gene expression require the tethering or folding of chromosomes (Uhlmann, 2016; Onn et al., 2008). Remarkably, these differ- ent types of chromosome organizations are all mediated by a conserved family of protein complexes *For correspondence: [email protected] called structural maintenance of chromosomes (SMC) (Onn et al., 2008; Nolivos and Sherratt, 2014; Hirano, 2016; Hassler et al., 2018). SMC complexes tether and fold chromosomes by two Competing interests: The activities. -
Mitotic Arrest Deficient 2 Expression Induces Chemosensitization to a DNA-Damaging Agent, Cisplatin, in Nasopharyngeal Carcinoma Cells
Research Article Mitotic Arrest Deficient 2 Expression Induces Chemosensitization to a DNA-Damaging Agent, Cisplatin, in Nasopharyngeal Carcinoma Cells Hiu Wing Cheung,1 Dong-Yan Jin,2 Ming-tat Ling,1 Yong Chuan Wong,1 Qi Wang,1 Sai Wah Tsao,1 and Xianghong Wang1 Departments of 1Anatomy and 2Biochemistry, Faculty of Medicine, University of Hong Kong, Hong Kong, China Abstract mitotic checkpoint control, may be associated with tumorigenesis Recently, mitotic arrest deficient 2 (MAD2)–mediated spindle as well as cancer progression. Several regulators of the mitotic checkpoint have been identified checkpoint is shown to induce mitotic arrest in response to DNA damage, indicating overlapping roles of the spindle and most of them are localized to the kinetochore, which is checkpoint and DNA damage checkpoint. In this study, we connected to both the chromosome and the spindle (1). One of investigated if MAD2 played a part in cellular sensitivity to them, mitotic arrest deficient 2 (MAD2), is thought to be a key DNA-damaging agents, especially cisplatin, and whether it was component for a functional mitotic checkpoint because it is regulated through mitotic checkpoint. Using nine nasopha- required for generating the ‘‘wait’’ signal in response to microtubule ryngeal carcinoma (NPC) cell lines, we found that decreased disruption (1). Deletion or down-regulation of MAD2 leads to MAD2 expression was correlated with cellular resistance to mitotic checkpoint inactivation and chromosomal instability (4–6). cisplatin compared with the cell lines with high levels of Down-regulation of MAD2 has also been reported in human MAD2. Exogenous MAD2 expression in NPC cells also cancers such as lung (7), breast (8), nasopharyngeal (9), and ovarian conferred sensitivity to DNA-damaging agents especially carcinomas (10). -
Polo-Like Kinase 1: Target and Regulator of Anaphase-Promoting Complex/Cyclosome–Dependent Proteolysis Frank Eckerdt1 and Klaus Strebhardt2
Review Polo-Like Kinase 1: Target and Regulator of Anaphase-Promoting Complex/Cyclosome–Dependent Proteolysis Frank Eckerdt1 and Klaus Strebhardt2 1Department of Pharmacology, University of Colorado School of Medicine, Denver, Colorado and 2Department of Gynecology and Obstetrics, Medical School, J.W. Goethe-University, Frankfurt, Germany Abstract to the regulation of the APC/C, an E3 ubiquitin ligase that is Polo-like kinase 1 (Plk1) is a key regulator of progression responsible for the timely destruction of various mitotic proteins, through mitosis. Although Plk1 seems to be dispensable for thereby regulating chromosome segregation, exit from mitosis, entry into mitosis, its role in spindle formation and exit from and a stable subsequent G1 phase (3).The APC/C is first activated by the ancillary protein Cdc20, targeting proteins containing a mitosis is crucial. Recent evidence suggests that a major role Cdc20 of Plk1 in exit from mitosis is the regulation of inhibitors of destruction box (D box), like securin.Once APC/C has the anaphase-promoting complex/cyclosome (APC/C), such as initiated mitotic exit, Cdc20 itself is degraded and is replaced by Cdh1, allowing the degradation of a wider spectrum of substrates. the early mitotic inhibitor 1 (Emi1) and spindle checkpoint Cdh1 proteins. Thus, Plk1 and the APC/C control mitotic regulators The APC/C complex targets not only D box–containing proteins but also proteins exhibiting a KEN box and/or an A box by both phosphorylation and targeted ubiquitylation to Cdh1 ensure the fidelity of chromosome separation at the meta- (e.g., cyclin B1 and Aurora A). Plk1 itself is an APC/C target. -
Mitosin/CENP-F in Mitosis, Transcriptional Control, and Differentiation
Journal of Biomedical Science (2006) 13: 205–213 205 DOI 10.1007/s11373-005-9057-3 Mitosin/CENP-F in mitosis, transcriptional control, and differentiation Li Ma1,2, Xiangshan Zhao1 & Xueliang Zhu1,* 1Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; 2Graduate School of Chinese Academy of Sciences, Beijing, 100039, China Ó 2006 National Science Council, Taipei Key words: differentiation, kinetochore, mitosis, transcription Summary Mitosin/CENP-F is a large nuclear/kinetochore protein containing multiple leucine zipper motifs poten- tially for protein interactions. Its expression levels and subcellular localization patterns are regulated in a cell cycle-dependent manner. Recently, accumulating lines of evidence have suggested it a multifunctional protein involved in mitotic control, microtubule dynamics, transcriptional regulation, and muscle cell differentiation. Consistently, it is shown to interact directly with a variety of proteins including CENP-E, NudE/Nudel, ATF4, and Rb. Here we review the current progress and discuss possible mechanisms through which mitosin may function. Mitosin, also named CENP-F, was initially iden- acid residues (GenBank Accession No. CAH73032) tified as a human autoimmune antigen [1, 2] and [3]. The gene expression is cell cycle-dependent, as an in vitro binding protein of the tumor suppressor the mRNA levels increase following S phase Rb [3, 4]. Its dynamic temporal expression and progression and peak in early M phase [3]. Such modification patterns as well as ever-changing patterns are regulated by the Forkhead transcrip- spatial distributions following the cell cycle pro- tion factor FoxM1 [5].