DOCSLIB.ORG

Chromosome Segregation in Budding Yeast: Sister Chromatid Cohesion and Related Mechanisms

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chromosome Segregation in Budding Yeast: Sister Chromatid Cohesion and Related Mechanisms YEASTBOOK Chromosome Segregation in Budding Yeast: Sister Chromatid Cohesion and Related Mechanisms Adele L. Marston The Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3JR, United Kingdom ABSTRACT Studies on budding yeast have exposed the highly conserved mechanisms by which duplicated chromosomes are evenly distributed to daughter cells at the metaphase–anaphase transition. The establishment of proteinaceous bridges between sister chromatids, a function provided by a ring-shaped complex known as cohesin, is central to accurate segregation. It is the destruction of this cohesin that triggers the segregation of chromosomes following their proper attachment to microtubules. Since it is irreversible, this process must be tightly controlled and driven to completion. Furthermore, during meiosis, modifications must be put in place to allow the segregation of maternal and paternal chromosomes in the first division for gamete formation. Here, I review the pioneering work from budding yeast that has led to a molecular understanding of the establishment and destruction of cohesion. TABLE OF CONTENTS Abstract 31 Introduction 32 Building Mitotic Chromosomes 32 Structure and function of the cohesin complex 32 Discovery of cohesion: 32 The cohesin ring: 33 How does cohesin hold chromosomes together?: 34 Loading cohesin onto chromosomes 34 The pattern of cohesin localization on chromosomes: 35 The cohesin loading reaction: 36 Replication–coupled establishment of cohesion 37 Eco1-directed cohesion establishment: 37 Other factors involved in cohesion establishment: 38 DNA damage-induced cohesion 39 Other structural components of chromosomes 39 The condensin complex: 40 Topoisomerase II: 40 Establishment of Biorientation 40 Role of kinetochore geometry and centromere structure 41 Continued Copyright © 2014 by the Genetics Society of America doi: 10.1534/genetics.112.145144 Manuscript received July 24, 2013; accepted for publication September 18, 2013 Available freely online through the author-supported open access option. Address for correspondence: School of Biological Sciences, Michael Swann Building, Mayfield Rd., Edinburgh EH9 3JR, United Kingdom. E-mail: [email protected] Genetics, Vol. 196, 31–63 January 2014 31 CONTENTS, continued Error correction 42 Destruction of Sister Chromatid Cohesion and Anaphase Onset 43 Cleavage of cohesin by separase 43 The spindle checkpoint 43 Inhibition of APC–Cdc20: 43 Checkpoint silencing: 45 Other factors regulating anaphase onset 45 Anaphase Progression 46 Separase initiates mitotic exit 46 Committing to anaphase: 47 Nuclear position: 47 Completion of chromosome segregation: 47 Maintaining spindle integrity: 48 Chromosome Segregation During Meiosis 48 Establishment of links between homologs during meiosis I 49 Homologous chromosome pairing: 49 Meiotic recombination: 49 Monoorientation of sister chromatids during meiosis I 50 Stepwise loss of cohesion 51 Biorientation of homologs 51 Alteration of cell cycle controls in meiosis 52 Meiotic prophase I to meiosis I transition: 52 Meiosis I to meiosis II transition: 52 Perspectives 53 URING cell division, chromosomes must be replicated yeast that led to an understanding of the molecular biology Dexactly and accurately distributed into daughter cells. of chromosome segregation together with the exquisite con- The regulated sequence of events that leads to cell division is trols that ensure its accuracy and the modifications that take known as the cell cycle. In S phase of the cell cycle, DNA place to generate gametes. synthesis and the establishment of sister chromatid cohesion generates two identical sister chromatids that are held Building Mitotic Chromosomes tightly together by a conserved protein complex, known as Structure and function of the cohesin complex cohesin. In mitosis, the cohesin linkages provide resistance and generate tension to facilitate the attachment of sister Discovery of cohesion: Pioneering studies in budding yeast chromatids to microtubules emanating from opposite poles. were instrumental in the discovery of the chromosome Once all the chromosomes have properly attached to micro- segregation machinery that is conserved in all eukaryotes. tubules, an enzyme known as separase becomes active and Early on, it was recognized that the two sister chromatids cleaves cohesin, thereby triggering the separation of sister must be held tightly together at metaphase to resist spindle chromatids to opposite poles (Figure 1). This process is forces, thereby allowing their attachment to microtubules modified during meiosis, which produces haploid gametes from opposite poles. However, the nature of this cohesion from a diploid progenitor cell. During meiosis, two rounds of was not known and two general models were put forward. chromosome segregation follow a single S phase. In meiosis One model postulated that the intertwining of sister DNA I, the maternal and paternal chromosomes, called homologs, molecules, perhaps due to the persistence of catenations are segregated, whereas sister chromatids are segregated after DNA replication, might provide cohesion (Murray and during meiosis II, which resembles mitosis (Figure 2). To Szostak 1985). Another, not mutually exclusive, model pro- achieve this, an additional layer of regulation must be in- posed the existence of proteins that generate molecular troduced. While conserved in eukaryotes, what we know bridges between sister chromatids. However, testing these about the molecular biology of chromosome segregation is models relied on the establishment of an assay for sister derived largely from work on the budding yeast Saccharo- chromatid cohesion. This was initially achieved by the de- myces cerevisiae. Here I review the discoveries in budding velopment of a fluorescence in situ hybridization assay 32 A. L. Marston Figure 1 Chromosome segregation during mito- sis. Schematic diagram showing the key features of chromosome segregation during budding yeast mitosis. (FISH) in yeast (Koshland and Hartwell 1987). Using this tains a signature motif that is required for the activity of ABC assay, it was shown that minichromosomes are cohesed at family ATPases. Smc1 NBD crystallized as a dimer with ATP metaphase even though they lack catenations, dispelling the sandwiched between the Walker A motif of one monomer idea that DNA catenation was sufficient to provide the and the signature motif on the other. In reality, Smc1 and “glue” (Koshland and Hartwell 1987; Guacci et al. 1994). Smc3 heterodimerize at their hinge domains to create This prompted the search for proteins that might mediate a V-shaped structure (Anderson et al. 2002; Haering et al. cohesion. A key technical development was the ingenious 2002). Therefore, the most likely arrangement is that two development of a method to label a single chromosome by molecules of ATP are sandwiched between the Smc1 and integration of tandem repeats of bacterial lacO, to which Smc3 NBDs. Consistently, fluorescence resonance energy ectopically produced LacI–GFP binds (Straight et al. 1996). transfer (FRET) experiments indicated that Smc1 and A similar system was developed using tetO and TetR–GFP Smc3 NBD domains are in close proximity (Mc Intyre et al. (Michaelis et al. 1997). The availability of these methods to 2007). label single chromosomes enabled the first cohesion proteins The kleisin subunit, Scc1, forms a bridge between the to be identified (Guacci et al. 1997; Michaelis et al. 1997). NBDs of the Smc1–Smc3 heterodimer, making contacts with These elegant studies isolated mutants incapable of main- Smc3 at its N terminus and Smc1 at its C terminus (Haering taining sister chromatid cohesion when arrested in mitosis. et al. 2002). A crystal structure revealed that the Scc1 C Subsequent studies revealed that sister chromatid cohesion terminus forms a winged helix domain that contacts the genes fall into functional classes (Table 1). One class of Smc1 NBD and mutations in this interface demonstrated genes encodes the proteins that make up the structural com- that this interaction is essential (Haering et al. 2004). In- ponent of cohesion, called cohesin. Others are accessory, terestingly, prior binding of the Scc1 C terminus to the Smc1 loading, or establishment factors. Remarkable progress has NBD is required for the Scc1 N terminus to bind the Smc3 been made in understanding how these many gene products NBD (Arumugam et al. 2003; Haering et al. 2004). This may interact to generate sister chromatid cohesion. ensure that a single molecule of Scc1 binds to the Smc1– Smc3 heterodimer. Although ATP binding to Smc1’s NBD is The cohesin ring: The core structural component of cohesin required for binding to the Scc1 C terminus, the interaction forms a ring, composed of two structural maintenance of of Scc1’s N terminus with Smc3 does not require ATP chromosome (SMC) proteins, Smc1 and Smc3, and a “klei- (Arumugam et al. 2003; Gruber et al. 2003). An explanation sin” (from the Greek for closure) subunit, Scc1/Mcd1 for this observation is offered by the arrangement of a bacte- (Guacci et al. 1997; Michaelis et al. 1997; Losada et al. rial Smc–kleisin complex. While the C terminus of a bacterial 1998) (Figure 3). A meiosis-specific kleisin, Rec8, replaces kleisin contacts the ATPase head of one Smc protein, its N Scc1 in meiotic cells and plays several roles important for terminus associates with the coil-coiled domain of the other the segregation of homologous chromosomes (see below). Smc subunit (Bürmann et al.
Load more

Recommended publications
  • 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
    [Show full text]
  • 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.
    [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]
  • 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.
    [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]
  • 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]
  • Chromosome Segregation: Learning Only When Chromosomes Are Correctly Bi-Oriented and Microtubules Exert to Let Go Tension Across Sister Kinetochores [6]
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Dispatch R883 an mTORC1 substrate that negatively regulates inhibitors. Oncogene http://dx.doi.org/10.1038/ 1Department of Cancer and Cell Biology, insulin signaling. Science 332, 1322–1326. onc.2013.92. University of Cincinnati College of Medicine, 16. Chung, J., Kuo, C.J., Crabtree, G.R., and 19. She, Q.B., Halilovic, E., Ye, Q., Zhen, W., Cincinnati, OH 45267, USA. 2Institute for Blenis, J. (1992). Rapamycin-FKBP specifically Shirasawa, S., Sasazuki, T., Solit, D.B., and blocks growth-dependent activation of and Rosen, N. (2010). 4E-BP1 is a key effector of the Research in Immunology and Cancer (IRIC), signaling by the 70 kd S6 protein kinases. Cell oncogenic activation of the AKT and ERK Universite´ de Montre´ al, Montreal, 69, 1227–1236. signaling pathways that integrates their Quebec H3C 3J7, Canada. 3Department of 17. Zhang, Y., and Zheng, X.F. (2012). function in tumors. Cancer Cell 18, Pathology and Cell Biology, Faculty of mTOR-independent 4E-BP1 phosphorylation is 39–51. Medicine, Universite´ de Montre´ al, Montreal, associated with cancer resistance to mTOR 20. Shin, S., Wolgamott, L., Tcherkezian, J., kinase inhibitors. Cell Cycle 11, 594–603. Vallabhapurapu, S., Yu, Y., Roux, P.P., and Quebec, H3C 3J7, Canada. 18. Ducker, G.S., Atreya, C.E., Simko, J.P., Yoon, S.O. (2013). Glycogen synthase E-mail: [email protected], philippe. Hom, Y.K., Matli, M.R., Benes, C.H., Hann, B., kinase-3beta positively regulates protein [email protected] Nakakura, E.K., Bergsland, E.K., Donner, D.B., synthesis and cell proliferation through the et al.
    [Show full text]
  • Shaping of the 3D Genome by the Atpase Machine Cohesin Yoori Kim1 and Hongtao Yu1,2
    Kim and Yu Experimental & Molecular Medicine (2020) 52:1891–1897 https://doi.org/10.1038/s12276-020-00526-2 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Shaping of the 3D genome by the ATPase machine cohesin Yoori Kim1 and Hongtao Yu1,2 Abstract The spatial organization of the genome is critical for fundamental biological processes, including transcription, genome replication, and segregation. Chromatin is compacted and organized with defined patterns and proper dynamics during the cell cycle. Aided by direct visualization and indirect genome reconstruction tools, recent discoveries have advanced our understanding of how interphase chromatin is dynamically folded at the molecular level. Here, we review the current understanding of interphase genome organization with a focus on the major regulator of genome structure, the cohesin complex. We further discuss how cohesin harnesses the energy of ATP hydrolysis to shape the genome by extruding chromatin loops. Introduction dynamic and preferentially form at certain genomic loci to The diploid human genome contains 46 chromosomes regulate gene expression and other DNA transactions. In and 6 billion nucleotides of DNA that, when fully exten- this article, we review our current understanding of the ded, span a length of over 2 m. The genomic DNA has to local and global landscapes of interphase chromatin and fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; be folded and con ned in the nucleus, which has a discuss how cohesin structures chromatin. dimension of ~10 μm. The compaction of genomic DNA also needs to be dynamic and orderly to allow myriad Local folding of interphase chromatin biochemical reactions that occur on the DNA template, Until recently, the dominant hypothesis for genome including DNA replication and repair, homologous packaging was the hierarchical folding model.
    [Show full text]
  • Accurate Chromosome Segregation by Probabilistic Self-Organisation Yasushi Saka1*, Claudiu V
    Saka et al. BMC Biology (2015) 13:65 DOI 10.1186/s12915-015-0172-y RESEARCH ARTICLE Open Access Accurate chromosome segregation by probabilistic self-organisation Yasushi Saka1*, Claudiu V. Giuraniuc1 and Hiroyuki Ohkura2* Abstract Background: For faithful chromosome segregation during cell division, correct attachments must be established between sister chromosomes and microtubules from opposite spindle poles through kinetochores (chromosome bi-orientation). Incorrect attachments of kinetochore microtubules (kMTs) lead to chromosome mis-segregation and aneuploidy, which is often associated with developmental abnormalities such as Down syndrome and diseases including cancer. The interaction between kinetochores and microtubules is highly dynamic with frequent attachments and detachments. However, it remains unclear how chromosome bi-orientation is achieved with such accuracy in such a dynamic process. Results: To gain new insight into this essential process, we have developed a simple mathematical model of kinetochore–microtubule interactions during cell division in general, i.e. both mitosis and meiosis. Firstly, the model reveals that the balance between attachment and detachment probabilities of kMTs is crucial for correct chromosome bi-orientation. With the right balance, incorrect attachments are resolved spontaneously into correct bi-oriented conformations while an imbalance leads to persistent errors. In addition, the model explains why errors are more commonly found in the first meiotic division (meiosis I) than in mitosis and how a faulty conformation can evade the spindle assembly checkpoint, which may lead to a chromosome loss. Conclusions: The proposed model, despite its simplicity, helps us understand one of the primary causes of chromosomal instability—aberrant kinetochore–microtubule interactions. The model reveals that chromosome bi-orientation is a probabilistic self-organisation, rather than a sophisticated process of error detection and correction.
    [Show full text]
  • Branching Out: Meiotic Recombination and Its Regulation
    TICB-453; No of Pages 8 Review TRENDS in Cell Biology Vol.xxx No.x Branching out: meiotic recombination and its regulation Gareth A. Cromie and Gerald R. Smith Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA Homologous recombination is a dynamic process by parental chromosome segregation during the first meiotic which DNA sequences and strands are exchanged. In division. The COs link the homologous chromosomes phy- meiosis, the reciprocal DNA recombination events called sically so that they can be oriented correctly on the meiotic crossovers are central to the generation of genetic diver- spindle. In the absence of COs, chromosomes often mis- sity in gametes and are required for homolog segregation segregate, resulting in aneuploid gametes and offspring. in most organisms. Recent studies have shed light on how Recent studies have advanced our understanding of how meiotic crossovers and other recombination products meiotic COs and NCOs form, how they are distributed form, how their position and number are regulated and across genomes, and how the pair of DNA molecules under- how the DNA molecules undergoing recombination are going a CO is chosen. In this review, we focus on how chosen. These studies indicate that the long-dominant, advances in these three areas have challenged several core unifying model of recombination proposed by Szostak features of long-accepted models, revealing many new et al. applies, with modification, only to a subset of branches of the meiotic recombination ‘pathway’. Most recombination events. Instead, crossover formation and significantly, the mechanism of recombination associated its control involve multiple pathways, with considerable with the well-known DSB repair model of Szostak et al.
    [Show full text]
  • The Emerging Role of Cohesin in the DNA Damage Response
    G C A T T A C G G C A T genes Review The Emerging Role of Cohesin in the DNA Damage Response Ireneusz Litwin * , Ewa Pilarczyk and Robert Wysocki Institute of Experimental Biology, University of Wroclaw, 50-328 Wroclaw, Poland; [email protected] (E.P.); [email protected] (R.W.) * Correspondence: [email protected]; Tel.: +48-71-375-4126 Received: 29 October 2018; Accepted: 21 November 2018; Published: 28 November 2018 Abstract: Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex whose canonical function is to hold sister chromatids together from S-phase until the onset of anaphase to ensure the equal division of chromosomes. However, recent research points to a crucial function of cohesin in the DNA damage response (DDR). In this review, we summarize recent advances in the understanding of cohesin function in DNA damage signaling and repair. First, we focus on cohesin architecture and molecular mechanisms that govern sister chromatid cohesion. Next, we briefly characterize the main DDR pathways. Finally, we describe mechanisms that determine cohesin accumulation at DNA damage sites and discuss possible roles of cohesin in DDR. Keywords: cohesin; cohesin loader; DNA double-strand breaks; replication stress; DNA damage tolerance 1. Introduction Genomes of all living organisms are continuously challenged by endogenous and exogenous insults that threaten genome stability. It has been estimated that human cells suffer more than 70,000 DNA lesions per day, most of which are single-strand DNA breaks (SSBs) [1].
    [Show full text]
  • 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.
    [Show full text]