Anaphase Bridges: Not All Natural Fibers Are Healthy

Total Page:16

File Type:pdf, Size:1020Kb

Anaphase Bridges: Not All Natural Fibers Are Healthy G C A T T A C G G C A T genes Review Anaphase Bridges: Not All Natural Fibers Are Healthy Alice Finardi 1, Lucia F. Massari 2 and Rosella Visintin 1,* 1 Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; alice.fi[email protected] 2 The Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; [email protected] * Correspondence: [email protected]; Tel.: +39-02-5748-9859; Fax: +39-02-9437-5991 Received: 14 July 2020; Accepted: 5 August 2020; Published: 7 August 2020 Abstract: At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and segregation, sister chromatids must be recognized as such and kept together until their separation. This process of cohesion is mainly achieved through proteinaceous linkages of cohesin complexes, which are loaded on the sister chromatids as they are generated during S phase. Cohesion between sister chromatids must be fully removed at anaphase to allow chromosome segregation. Other (non-proteinaceous) sources of cohesion between sister chromatids consist of DNA linkages or sister chromatid intertwines. DNA linkages are a natural consequence of DNA replication, but must be timely resolved before chromosome segregation to avoid the arising of DNA lesions and genome instability, a hallmark of cancer development. As complete resolution of sister chromatid intertwines only occurs during chromosome segregation, it is not clear whether DNA linkages that persist in mitosis are simply an unwanted leftover or whether they have a functional role. In this review, we provide an overview of DNA linkages between sister chromatids, from their origin to their resolution, and we discuss the consequences of a failure in their detection and processing and speculate on their potential role. Keywords: SCI; anaphase bridges; topoisomerases; catenane 1. Sister Chromatid Intertwines: Structure, Origin and Resolution Sister chromatid intertwines (SCIs) represent an additional source of cohesion between the chromatids. They arise during DNA replication and must be removed before cell division to preserve genome integrity. SCIs are usually classified based on their molecular structure, which reflects their origin. Three types of intertwines are recognized, namely short regions of un-replicated DNA, recombination intermediates and DNA catenanes (Figure1A). Irrespectively of their nature and location in the genome, SCIs naturally arise during DNA replication and are mainly resolved in S phase, although some do persist and must be fully removed during mitosis to allow faithful chromosome segregation. Intertwines that persist through mitosis manifest themselves as DNA threads stretching between the two segregating DNA masses, known as anaphase bridges (Figure1). Genes 2020, 11, 902; doi:10.3390/genes11080902 www.mdpi.com/journal/genes Genes 2020, 11, 902 2 of 29 Genes 2019, 10, x FOR PEER REVIEW 2 of 29 Figure 1. Three types of sister chromatid intertwines (SCIs) are observed during mitosis. (A) Molecular structuresFigure 1. ofThree late replicationtypes of sister intermediates, chromatid joint intertwines molecules (SCIs) (here are exemplified observed by during a double mitosis. Holliday (A) junction)Molecular and structures catenanes of arelate shown. replication Genomic intermedia loci at whichtes, joint each molecules type of SCI (here were exemplified observed are by indicateda double inHolliday the schematic junction) chromosomes. and catenanes The are consequence shown. Genomic of persistent loci at SCIs whic inh mitosiseach type – a.k.a. of SCI anaphase were observed bridges –are is shownindicated in the in drawnthe schematic cell. (B, Cchromosomes.) Representative The images consequence of (B) a chromatin of persistent bridge SCIs and in (Cmitosis) an ultra-fine – a.k.a. bridgeanaphase are bridges shown in– is retinal shown pigment in the drawn epithelium cell. ( (RPE-1)B,C) Representative cells. DNA-intercalating images of (B dye) a chromatin Hoechst in bridge cyan, Plk1-interactingand (C) an ultra-fine checkpoint bridge are helicase shown (PICH) in retinal in magenta.pigment epithelium Courtesy images (RPE-1) by cells. Neal DNA-intercalating Umbreit (B) and Mitchelldye Hoechst Leibowitz in cyan, (C). Plk1-interacting checkpoint helicase (PICH) in magenta. Courtesy images by Neal Umbreit (B) and Mitchell Leibowitz (C). Although the number of anaphase bridges increases in the presence of stress, such as treatment with replicationAlthough inhibitors the number or impairment of anaphase of DNA bridges repair increase pathways,s in the DNA presence bridges of arestress, observed such as even treatment in the absencewith replication of stressors inhibitors and in untransformedor impairment cells,of DNA especially repair pathways, at the centromeres DNA bridges in mammalian are observed cells even [1,2]. Inin addition,the absence anaphase of stressors bridges and also in untransformed form when cells cells, attempt especially to segregate at the dicentriccentromeres chromosomes in mammalian that resultcells [1,2]. from telomere-to-telomereIn addition, anaphase fusion bridges [3–5]. also In contrast form towhen the othercells classesattempt of SCIs,to segregate which are dicentric thought tochromosomes occur during that normal result DNA from metabolism,telomere-to-telomere telomere fusion fusions [3–5]. are triggered In contrast by to telomere the other disfunction, classes of whichSCIs, which can be are caused thought by excessive to occur during telomere normal shortening DNA ormetabolism, by malfunctioning telomere of fusions the sheltering are triggered complex by thattelomere protects disfunction, chromosome which ends can (reviewed be caused in by Reference excessive [ 6telomere]). shortening or by malfunctioning of the shelteringAnaphase complex bridges canthat be protects classified chro asmosome either chromatin ends (reviewed bridges in or Reference ultra-fine bridges[6]). (UFBs), based on whetherAnaphase or not bridges the DNA can isbe chromatinized classified as (i.e.,either packaged chromatin with bridges histones or and ultra-fine other proteins) bridges and(UFBs), can bebased stained on whether with DNA or not dyes the like DNA Hoechst is chromatinized (Figure1B,C). (i.e., In unperturbedpackaged with conditions, histones and chromatin other proteins) bridges areand rare can and,be stained in yeast, with they DNA are dyes mostly like attributed Hoechst (F toigure unresolved 1B,C). In recombination unperturbed conditions, intermediates chromatin [7]. On thebridges other are hand, rare UFBsand, in can yeast, be observed they are inmostly the majority attributed of to cells unresolved in anaphase, recombination and they are intermediates enriched at the[7]. centromereOn the other in hand, human UFBs cells can [1,7 ].be The observed samekind in the of majority stressor canof cells often in induce anaphase, formation and they of both are typesenriched of bridges at the centromere (i.e., chromatinized in human and cells non-chromatinized), [1,7]. The same kind suggesting of stressor thatcan bothoften caninduce arise formation from the sameof both kind types of DNAof bridges intertwining. (i.e., chromatinized Currently, it and is not non-chromatinize clear what determinesd), suggesting the chromatinized that both can status arise of from the same kind of DNA intertwining. Currently, it is not clear what determines the chromatinized status of DNA bridges. Chromatin bridges may evolve into UFBs, according to the stage of their Genes 2020, 11, 902 3 of 29 DNA bridges. Chromatin bridges may evolve into UFBs, according to the stage of their resolution. Alternatively, the chromatinized status of a bridge may be determined at the time of its formation. In the latter case, DNA chromatinization may depend on several factors, such as the extent of intertwining or the timing of recognition during mitosis. Certain DNA intertwines are more commonly retained at specific loci. However, since different types of linkages can form anaphase bridges at the same region, their position in the genome is not sufficient to infer their molecular structure. 1.1. Incomplete Replication and Recombination Intermediates Un-replicated regions provide a source of DNA linkages called late-replication intermediates (LRIs). LRIs are bonds between the two—otherwise fully replicated—sister chromatids and consist of short un-replicated double-stranded DNA (dsDNA) segments, where the two parental strands still anneal to each other. Since replication is generally completed well before anaphase, LRIs usually do not evolve into anaphase bridges. Instead, anaphase bridges can form in conditions of replication stress, preferentially at late replicating or hard-to-replicate regions, like common fragile sites (CFSs) [2]. Indeed, in human cells, replication of fragile sites is often left incomplete, particularly under conditions of replicative stress, leading to DNA damage in the next cell cycle [8,9]. Another region that poses a challenge to replication is the telomere, as it contains repeated DNA sequences and tends to form G-quadruplexes, secondary DNA structures that can stall the replication fork. Consistently, telomeric anaphase bridges increase if replication of these regions is impaired, for example by depletion of the Werner helicase, which contributes to the resolution of G-quadruplexes
Recommended publications
  • How Human H1 Histone Recognizes DNA
    molecules Article How Human H1 Histone Recognizes DNA Olesya P. Luzhetskaya, Sergey E. Sedykh and Georgy A. Nevinsky * Institute of Chemical Biology and Fundamental Medicine, SD of Russian Academy of Sciences, 8 Lavrentiev Ave., 630090 Novosibirsk, Russia; [email protected] (O.P.L.); [email protected] (S.E.S.) * Correspondence: [email protected]; Tel.: +7-383-363-51-26; Fax: +7-383-363-51-53 Received: 11 August 2020; Accepted: 1 October 2020; Published: 5 October 2020 Abstract: Linker H1 histone is one of the five main histone proteins (H1, H2A, H2B, H3, and H4), which are components of chromatin in eukaryotic cells. Here we have analyzed the patterns of DNA recognition by free H1 histone using a stepwise increase of the ligand complexity method; the affinity of H1 histone for various single- and double-stranded oligonucleotides (d(pN)n; n = 1–20) was evaluated using their competition with 12-mer [32P]labeled oligonucleotide and protein–oligonucleotide complex delaying on nitrocellulose membrane filters. It was shown that minimal ligands of H1 histone (like other DNA-dependent proteins and enzymes) are different mononucleotides (dNMPs; Kd = (1.30 0.2) 2 ± 10 M). An increase in the length of single-stranded (ss) homo- and hetero-oligonucleotides (d(pA)n, × − d(pT)n, d(pC)n, and d(pN)n with different bases) by one nucleotide link regardless of their bases, leads to a monotonic increase in their affinity by a factor of f = 3.0 0.2. This factor f corresponds ± to the Kd value = 1/f characterizing the affinity of one nucleotide of different ss d(pN)n for H1 at n = 2–6 (which are covered by this protein globule) is approximately 0.33 0.02 M.
    [Show full text]
  • GENETICS and GENOMICS Ed
    GENETICS AND GENOMICS Ed. Csaba Szalai, PhD GENETICS AND GENOMICS Editor: Csaba Szalai, PhD, university professor Authors: Chapter 1: Valéria László Chapter 2, 3, 4, 6, 7: Sára Tóth Chapter 5: Erna Pap Chapter 8, 9, 10, 11, 12, 13, 14: Csaba Szalai Chapter 15: András Falus and Ferenc Oberfrank Keywords: Mitosis, meiosis, mutations, cytogenetics, epigenetics, Mendelian inheritance, genetics of sex, developmental genetics, stem cell biology, oncogenetics, immunogenetics, human genomics, genomics of complex diseases, genomic methods, population genetics, evolution genetics, pharmacogenomics, nutrigenetics, gene environmental interaction, systems biology, bioethics. Summary The book contains the substance of the lectures and partly of the practices of the subject of ‘Genetics and Genomics’ held in Semmelweis University for medical, pharmacological and dental students. The book does not contain basic genetics and molecular biology, but rather topics from human genetics mainly from medical point of views. Some of the 15 chapters deal with medical genetics, but the chapters also introduce to the basic knowledge of cell division, cytogenetics, epigenetics, developmental genetics, stem cell biology, oncogenetics, immunogenetics, population genetics, evolution genetics, nutrigenetics, and to a relative new subject, the human genomics and its applications for the study of the genomic background of complex diseases, pharmacogenomics and for the investigation of the genome environmental interactions. As genomics belongs to sytems biology, a chapter introduces to basic terms of systems biology, and concentrating on diseases, some examples of the application and utilization of this scientific field are also be shown. The modern human genetics can also be associated with several ethical, social and legal issues. The last chapter of this book deals with these issues.
    [Show full text]
  • 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.
    [Show full text]
  • Chromatid Cohesion During Mitosis: Lessons from Meiosis
    Journal of Cell Science 112, 2607-2613 (1999) 2607 Printed in Great Britain © The Company of Biologists Limited 1999 JCS0467 COMMENTARY Chromatid cohesion during mitosis: lessons from meiosis Conly L. Rieder1,2,3 and Richard Cole1 1Wadsworth Center, New York State Dept of Health, PO Box 509, Albany, New York 12201-0509, USA 2Department of Biomedical Sciences, State University of New York, Albany, New York 12222, USA 3Marine Biology Laboratory, Woods Hole, MA 02543-1015, USA *Author for correspondence (e-mail: [email protected]) Published on WWW 21 July 1999 SUMMARY The equal distribution of chromosomes during mitosis and temporally separated under various conditions. Finally, we meiosis is dependent on the maintenance of sister demonstrate that in the absence of a centromeric tether, chromatid cohesion. In this commentary we review the arm cohesion is sufficient to maintain chromatid cohesion evidence that, during meiosis, the mechanism underlying during prometaphase of mitosis. This finding provides a the cohesion of chromatids along their arms is different straightforward explanation for why mutants in proteins from that responsible for cohesion in the centromere responsible for centromeric cohesion in Drosophila (e.g. region. We then argue that the chromatids on a mitotic ord, mei-s332) disrupt meiosis but not mitosis. chromosome are also tethered along their arms and in the centromere by different mechanisms, and that the Key words: Sister-chromatid cohesion, Mitosis, Meiosis, Anaphase functional action of these two mechanisms can be onset INTRODUCTION (related to the fission yeast Cut1P; Ciosk et al., 1998). When Pds1 is destroyed Esp1 is liberated, and this event somehow The equal distribution of chromosomes during mitosis is induces a class of ‘glue’ proteins, called cohesins (e.g.
    [Show full text]
  • Deciphering Nuclear Mechanobiology in Laminopathy
    cells Review Deciphering Nuclear Mechanobiology in Laminopathy Jungwon Hah and Dong-Hwee Kim * KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-3290-4615 Received: 29 January 2019; Accepted: 5 March 2019; Published: 11 March 2019 Abstract: Extracellular mechanical stimuli are translated into biochemical signals inside the cell via mechanotransduction. The nucleus plays a critical role in mechanoregulation, which encompasses mechanosensing and mechanotransduction. The nuclear lamina underlying the inner nuclear membrane not only maintains the structural integrity, but also connects the cytoskeleton to the nuclear envelope. Lamin mutations, therefore, dysregulate the nuclear response, resulting in abnormal mechanoregulations, and ultimately, disease progression. Impaired mechanoregulations even induce malfunction in nuclear positioning, cell migration, mechanosensation, as well as differentiation. To know how to overcome laminopathies, we need to understand the mechanisms of laminopathies in a mechanobiological way. Recently, emerging studies have demonstrated the varying defects from lamin mutation in cellular homeostasis within mechanical surroundings. Therefore, this review summarizes recent findings highlighting the role of lamins, the architecture of nuclear lamina, and their disease relevance in the context of nuclear mechanobiology. We will also provide an overview of the differentiation of cellular mechanics in laminopathy. Keywords: lamin; laminopathy; cytoskeleton; nucleus 1. Introduction Mechanical stimuli are the key to controlling numerous biological processes, including proliferation, differentiation, and migration [1–3]. Integrin mediates the transduction of forces from the external microenvironment to the intracellular cytoskeleton, and the nucleo-cytoskeletal molecular connections transmit the forces to the intranuclear chromosomal organizations [4,5].
    [Show full text]
  • 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.
    [Show full text]
  • Overview of Meiosis
    Sexual Reproduction and Meiosis Chapter 11 Overview of Meiosis Meiosis is a form of cell division that leads to the production of gametes. gametes: egg cells and sperm cells -contain half the number of chromosomes of an adult body cell Adult body cells (somatic cells) are diploid, containing 2 sets of chromosomes. Gametes are haploid, containing only 1 set of chromosomes. 2 Overview of Meiosis Sexual reproduction includes the fusion of gametes (fertilization) to produce a diploid zygote. Life cycles of sexually reproducing organisms involve the alternation of haploid and diploid stages. Some life cycles include longer diploid phases, some include longer haploid phases. 3 1 4 5 6 2 7 Features of Meiosis Meiosis includes two rounds of division – meiosis I and meiosis II. During meiosis I, homologous chromosomes (homologues) become closely associated with each other. This is synapsis. Proteins between the homologues hold them in a synaptonemal complex. 8 9 3 Features of Meiosis Crossing over: genetic recombination between non-sister chromatids -physical exchange of regions of the chromatids chiasmata: sites of crossing over The homologues are separated from each other in anaphase I. 10 Features of Meiosis Meiosis involves two successive cell divisions with no replication of genetic material between them. This results in a reduction of the chromosome number from diploid to haploid. 11 12 4 The Process of Meiosis Prophase I: -chromosomes coil tighter -nuclear envelope dissolves -homologues become closely associated in synapsis -crossing over
    [Show full text]
  • Aging Mice Have Increased Chromosome Instability That Is Exacerbated by Elevated Mdm2 Expression
    Oncogene (2011) 30, 4622–4631 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression T Lushnikova1, A Bouska2, J Odvody1, WD Dupont3 and CM Eischen1 1Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA; 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA and 3Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA Aging is thought to negatively affect multiple cellular Introduction processes including the ability to maintain chromosome stability. Chromosome instability (CIN) is a common Genomic instability refers to the accumulation or property of cancer cells and may be a contributing factor acquisition of numerical and/or structural abnormali- to cellular transformation. The types of DNA aberrations ties in chromosomes. It has long been observed that that arise during aging before tumor development and that chromosome instability (CIN) is a hallmark of cancer contribute to tumorigenesis are currently unclear. Mdm2, cells and is postulated to be required for tumorigenesis a key regulator of the p53 tumor suppressor and (Lengauer et al., 1998; Negrini et al., 2010). Genomic modulator of DNA break repair, is frequently over- changes, such as chromosome breaks, translocations, expressed in malignancies and contributes to CIN. To genome rearrangements, aneuploidy and telomere short- determine the relationship between aging and CIN and the ening have been observed in aging organisms (Nisitani role of Mdm2, precancerous wild-type C57Bl/6 and et al., 1990; Tucker et al., 1999; Dolle and Vijg, 2002; littermate-matched Mdm2 transgenic mice at various Aubert and Lansdorp, 2008; Zietkiewicz et al., 2009).
    [Show full text]
  • 1 Sister Chromatids Are Often Incompletely Cohesed In
    Genetics: Published Articles Ahead of Print, published on September 12, 2005 as 10.1534/genetics.105.048363 Sister chromatids are often incompletely cohesed in meristematic and endopolyploid interphase nuclei of Arabidopsis thaliana Veit Schubert, Marco Klatte, Ales Pecinka, Armin Meister, Zuzana Jasencakova1, Ingo Schubert2 Institute of Plant Genetics and Crop Plant Research (IPK), D-06466 Gatersleben, Germany 1present address: Dulbecco Telethon Institute of Genetics & Biophysics CNR, Epigenetics & Genome Reprogramming Laboratory, I-80131 Napoli, Italy 1 Running head: Sister chromatid alignment in Arabidopsis Keywords: Arabidopsis thaliana, sister chromatid cohesion, meristematic and endopolyploid nuclei, fluorescent in situ hybridization (FISH), 2Corresponding author: Ingo Schubert, Institute of Plant Genetics and Crop Plant Research (IPK), Corrensstrasse 3, D-06466 Gatersleben, Germany Telephone: +49-39482-5239 Fax: +49-39482-5137 e-mail: [email protected] 2 ABSTRACT We analysed whether sister chromatids are continuously cohesed in meristematic and endopolyploid Arabidopsis interphase nuclei by studying sister chromatid alignment at various chromosomal positions. FISH with individual BACs to flow-sorted 4C root and leaf nuclei frequently yielded more than two hybridization signals indicating incomplete or lacking sister chromatid alignment. Up to 100% of 8C, 16C and 32C nuclei showed no sister chromatid alignment at defined positions. Simultaneous FISH with BACs from different chromosomal positions revealed more frequent sister chromatid alignment in terminal than in mid arm positions. Centromeric positions were mainly aligned up to a ploidy level of 16C but became separated or dispersed in 32C nuclei. DNA hypomethylation (of the whole genome) and transcriptional activity (at FWA gene position) did not impair sister chromatid alignment. Only 6.1% of 4C leaf nuclei showed sister chromatid separation of entire chromosome 1 top arm territories.
    [Show full text]
  • 000466 SIMR REPRT Fall2k3
    NEWS AND THE INSIGHT FROM THE STOWERS INSTITUTE FOR MEDICAL Stowers RESEARCH REPORT FALL 2 0 0 Stowers Institute for Medical Research principal investigators who have received recent noteworthy awards and honors gather at the west end 3 of the Stowers Institute® campus. Front row, from left: Paul Trainor, Robb Krumlauf, Chunying Du. Second row, from left: Olivier Pourquié, Peter Baumann, Jennifer Gerton, Ting Xie. Ultimate solutions take time. Inside this issue . That’s particularly true with complex • Dr. Scott Hawley makes some surprising discoveries about how mistakes human diseases and birth defects during meiosis can lead to miscarriages and birth defects (Page 2). since there is still much we don’t • Dr. Olivier Pourquié sheds light on how the segments of the body begin to understand about the fundamentals grow at the right time and place in the embryo (Page 4). of life. At the Stowers Institute for • How do cells know when and where to differentiate and when their useful Medical Research, investigators healthy life is over? Dr. Chunying Du discovers a curious double negative seek to increase the understanding feedback loop in the apoptosis process that goes awry in cancer (Page 6); of the basic processes in living cells – Dr. Ting Xie investigates the importance of an environmental niche for VOLUME 6 stem cells (Page 7); and Dr. Peter Baumann studies the role of telomeres in a crucial step in the search for new aging and cancer (Page 8). medical treatments. • Scientific Director Dr. Robb Krumlauf and fellow Stowers Institute investigators inspire and are inspired by scientists and students in embryology at the Marine Biological Laboratory in Woods Hole, Massachusetts (Page 10).
    [Show full text]
  • Theory of DNA Condensation: Collapse Versus Aggregation
    Theory of DNA Condensation: Collapse Versus Aggregation CAROL BETH POST* and BRUNO H. ZIMM, Department of Chemistry, B-017, University of California at San Diego, La Jolla, California 92093 Synopsis In an unfavorable solvent environment, DNA (and other polymers) undergo a conforma- tional transition to a collapsed form, accompanied by a dramatic reduction in the effective volume of the molecule. Solvent conditions leading to the collapse are the same as those that cause aggregation. We give here a thermodynamic description of the collapse and its relations to aggregation (or precipitation). This is formulated in terms of the Flory-Huggins theory of the thermodynamics of polymer solutions. The results show that it is possible for three different states of DNA to be stable under different conditions: (1) the extended random coil, (2) the collapsed coil, and (3) a concentrated phase of aggregated random coils. The collapsed coil is predicted to he stable against aggregation only at high dilutions, of the order of parts per million. For DNA the transition between the extended coil and the collapsed coil is predicted to he discontinuous, in the sense that intermediate states are not present, because of the relatively high stiffness of the chain. The transition should appear diffuse because of the small size of the single molecule in comparison to macroscopic systems. INTRODUCTION In an unfavorable solvent environment there is a tendency for the seg- ments of a polymer chain to associate with other polymer segments, re- ducing their interaction with the solvent. These associations can be either intramolecular, leading to a collapsed structure of a single polymer chain, or intermolecular, leading to an aggregated polymer phase.
    [Show full text]
  • Mechanisms and Regulation of Mitotic Recombination in Saccharomyces Cerevisiae
    YEASTBOOK GENOME ORGANIZATION AND INTEGRITY Mechanisms and Regulation of Mitotic Recombination in Saccharomyces cerevisiae Lorraine S. Symington,* Rodney Rothstein,† and Michael Lisby‡ *Department of Microbiology and Immunology, and yDepartment of Genetics and Development, Columbia University Medical Center, New York, New York 10032, and ‡Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark ABSTRACT Homology-dependent exchange of genetic information between DNA molecules has a profound impact on the maintenance of genome integrity by facilitating error-free DNA repair, replication, and chromosome segregation during cell division as well as programmed cell developmental events. This chapter will focus on homologous mitotic recombination in budding yeast Saccharomyces cerevisiae.However, there is an important link between mitotic and meiotic recombination (covered in the forthcoming chapter by Hunter et al. 2015) and many of the functions are evolutionarily conserved. Here we will discuss several models that have been proposed to explain the mechanism of mitotic recombination, the genes and proteins involved in various pathways, the genetic and physical assays used to discover and study these genes, and the roles of many of these proteins inside the cell. TABLE OF CONTENTS Abstract 795 I. Introduction 796 II. Mechanisms of Recombination 798 A. Models for DSB-initiated homologous recombination 798 DSB repair and synthesis-dependent strand annealing models 798 Break-induced replication 798 Single-strand annealing and microhomology-mediated end joining 799 B. Proteins involved in homologous recombination 800 DNA end resection 800 Homologous pairing and strand invasion 802 Rad51 mediators 803 Single-strand annealing 803 DNA translocases 804 DNA synthesis during HR 805 Resolution of recombination intermediates 805 III.
    [Show full text]