Esco1 and Esco2 Regulate Distinct Cohesin Functions During Cell Cycle Progression
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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 -
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. -
The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
cancers Review The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Carini Picardi Morais de Castro 1, Maria Cadefau 1,2 and Sergi Cuartero 1,2,* 1 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] (C.P.M.d.C); [email protected] (M.C.) 2 Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain * Correspondence: [email protected] Simple Summary: Leukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy. Abstract: Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and Citation: de Castro, C.P.M.; Cadefau, in signalling mediators of the JAK/STAT and RAS pathways. -
Upon Microbial Challenge, Human Neutrophils Undergo Rapid Changes in Nuclear Architecture and Chromatin Folding to Orchestrate an Immediate Inflammatory Gene Program
Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Upon microbial challenge, human neutrophils undergo rapid changes in nuclear architecture and chromatin folding to orchestrate an immediate inflammatory gene program Matthew Denholtz,1,5 Yina Zhu,1,5 Zhaoren He,1 Hanbin Lu,1 Takeshi Isoda,1,4 Simon Döhrmann,2 Victor Nizet,2,3 and Cornelis Murre1 1Division of Biological Sciences, Department of Molecular Biology, University of California at San Diego, La Jolla, California 92039, USA; 2Department of Pediatrics, University of California at San Diego School of Medicine, La Jolla, California 92093, USA; 3Skaggs School of Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, USA Differentiating neutrophils undergo large-scale changes in nuclear morphology. How such alterations in structure are established and modulated upon exposure to microbial agents is largely unknown. Here, we found that prior to encounter with bacteria, an armamentarium of inflammatory genes was positioned in a transcriptionally passive environment suppressing premature transcriptional activation. Upon microbial exposure, however, human neu- trophils rapidly (<3 h) repositioned the ensemble of proinflammatory genes toward the transcriptionally permissive compartment. We show that the repositioning of genes was closely associated with the swift recruitment of cohesin across the inflammatory enhancer landscape, permitting an immediate transcriptional response upon bacterial exposure. We found that activated enhancers, marked by increased deposition of H3K27Ac, were highly enriched for cistromic elements associated with PU.1, CEBPB, TFE3, JUN, and FOSL2 occupancy. These data reveal how upon microbial challenge the cohesin machinery is recruited to an activated enhancer repertoire to instruct changes in chromatin folding, nuclear architecture, and to activate an inflammatory gene program. -
Structure of the Human Cohesin Inhibitor Wapl
Structure of the human cohesin inhibitor Wapl Zhuqing Ouyanga,1, Ge Zhenga,1, Jianhua Songb, Dominika M. Borekc, Zbyszek Otwinowskic, Chad A. Brautigamc, Diana R. Tomchickc, Susannah Rankinb, and Hongtao Yua,2 aHoward Hughes Medical Institute, Department of Pharmacology, and cDepartment of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and bProgram in Cell Cycle and Cancer Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104 Edited by Douglas Koshland, University of California, Berkeley, CA, and approved May 23, 2013 (received for review March 11, 2013) Cohesin, along with positive regulators, establishes sister-chromatid trigger cohesin release from chromosome arms (15, 18–21). A pool of cohesion by forming a ring to circle chromatin. The wings apart-like cohesin at centromeres is protected by the shugoshin (Sgo1)–protein protein (Wapl) is a key negative regulator of cohesin and forms phosphatase 2A (PP2A) complex (22, 23), which binds to cohesin, a complex with precocious dissociation of sisters protein 5 (Pds5) to dephosphorylates sororin, and protects cohesin from Wapl promote cohesin release from chromatin. Here we report the at centromeres (24). After all sister kinetochores attach properly crystal structure and functional characterization of human Wapl. to the mitotic spindle and are under tension, separase cleaves Wapl contains a flexible, variable N-terminal region (Wapl-N) and centromeric cohesin to initiate sister-chromatid separation. The a conserved C-terminal domain (Wapl-C) consisting of eight HEAT separated chromatids are evenly partitioned into the two daughter (Huntingtin, Elongation factor 3, A subunit, and target of rapamycin) cells through their attachment to microtubules originating from the repeats. -
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. -
Ultrasound-Assisted Nonviral Gene Transfer of AQP1 to the Irradiated Minipig Parotid Gland Restores fluid Secretion
Gene Therapy (2015) 22, 739–749 © 2015 Macmillan Publishers Limited All rights reserved 0969-7128/15 www.nature.com/gt ORIGINAL ARTICLE Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion Z Wang1, L Zourelias1,CWu1, PC Edwards2, M Trombetta3 and MJ Passineau1 Xerostomia is a common side effect of ionizing radiation used to treat head and neck cancer. A groundbreaking Phase I human clinical trial using Adenoviral gene transfer of Aquaporin-1 (AQP1) to a single salivary gland of individuals suffering from radiation- induced xerostomia has recently been reported. Unfortunately, the limitations of the Adenoviral vector system used in this pioneering trial preclude its advancement to a Phase II trial, and we have thus undertaken to evaluate the therapeutic potential of ultrasound-assisted nonviral gene transfer (UAGT) as an alternative means of delivering AQP1 gene therapy to the salivary gland by comparing head-to-head with the canonical Adenoviral vector in a swine model. Swine irradiated unilaterally with a 10-Gy electron beam targeted at the parotid gland suffered from significant, sustained hyposalivation that was bilateral, despite irradiation being confined to the targeted gland. Unilateral AQP1 gene therapy with UAGT resulted in bilateral restoration of stimulated salivary flow at 48 h and 1 week post treatment (1.62 ± 0.48 ml and 1.87 ± 0.45 ml) to preinjury levels (1.34 ± 0.14 ml) in a manner comparable to Adenoviral delivery (2.32 ± 0.6 ml and 1.33 ± 0.97 ml). UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy in the irradiated swine model, and it is a candidate for advancement to a Phase I human clinical trial. -
A Requirement for STAG2 in Replication Fork Progression Creates a Targetable Synthetic Lethality in Cohesin-Mutant Cancers
ARTICLE https://doi.org/10.1038/s41467-019-09659-z OPEN A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers Gourish Mondal1, Meredith Stevers1, Benjamin Goode 1, Alan Ashworth2,3 & David A. Solomon 1,2 Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that 1234567890():,; the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a con- sequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers. 1 Department of Pathology, University of California, San Francisco, CA 94143, USA. 2 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA. 3 Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, CA 94158, USA. Correspondence and requests for materials should be addressed to D.A.S. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1686 | https://doi.org/10.1038/s41467-019-09659-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09659-z ohesin is a multi-protein complex composed of four core transcriptional dysregulation22,23. -
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. -
Lecture9'21 Chromatin II
Genetic Organization -Chromosomal Arrangement: From Form to Function. Chapters 9 & 10 in Genes XI The Eukaryotic chromosome – Organized Structures -banding – Centromeres – Telomeres – Nucleosomes – Euchromatin / Heterochromatin – Higher Orders of Chromosomal Structure 2 Heterochromatin differs from euchromatin in that heterochromatin is effectively inert; remains condensed during interphase; is transcriptionally repressed; replicates late in S phase and may be localized to the centromere or nuclear periphery Facultative heterochromatin is not restricted by pre-designated sequence; genes that are moved within or near heterochromatic regions can become inactivated as a result of their new location. Heterochromatin differs from euchromatin in that heterochromatin is effectively inert; remains condensed during interphase; is transcriptionally repressed; replicates late in S phase and may be localized to the centromere or nuclear periphery Facultative heterochromatin is not restricted by pre-designated sequence; genes that are moved within or near heterochromatic regions can become inactivated as a result of their new location. Chromatin inactivation (or heterochromatin formation) occurs by the addition of proteins to the nucleosomal fiber. May be due to: Chromatin condensation -making it inaccessible to transcriptional apparatus Proteins that accumulate and inhibit accessibility to the regulatory sequences Proteins that directly inhibit transcription Chromatin Is Fundamentally Divided into Euchromatin and Heterochromatin • Individual chromosomes can be seen only during mitosis. • During interphase, the general mass of chromatin is in the form of euchromatin, which is slightly less tightly packed than mitotic chromosomes. TF20210119 Regions of compact heterochromatin are clustered near the nucleolus and nuclear membrane Photo courtesy of Edmund Puvion, Centre National de la Recherche Scientifique Chromatin: Basic Structures • nucleosome – The basic structural subunit of chromatin, consisting of ~200 bp of DNA wrapped around an octamer of histone proteins. -
THE DEVELOPMENT of CHEMICAL METHODS to DISCOVER KINASE SUBSTRATES and MAP CELL SIGNALING with GAMMA-MODIFIED ATP ANALOG-DEPENDENT KINASE-CATALYZED PHOSPHORYLATION By
Wayne State University Wayne State University Dissertations 1-1-2017 The evelopmeD nt Of Chemical Methods To Discover Kinase Substrates And Map Cell Signaling With Gamma-Modified Atp Analog- Dependent Kinase-Catalyzed Phosphorylation Dissanayaka Mudiyanselage Maheeka Madhubashini Embogama Wayne State University, Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Analytical Chemistry Commons, and the Biochemistry Commons Recommended Citation Embogama, Dissanayaka Mudiyanselage Maheeka Madhubashini, "The eD velopment Of Chemical Methods To Discover Kinase Substrates And Map Cell Signaling With Gamma-Modified Atp Analog-Dependent Kinase-Catalyzed Phosphorylation" (2017). Wayne State University Dissertations. 1698. https://digitalcommons.wayne.edu/oa_dissertations/1698 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. THE DEVELOPMENT OF CHEMICAL METHODS TO DISCOVER KINASE SUBSTRATES AND MAP CELL SIGNALING WITH GAMMA-MODIFIED ATP ANALOG-DEPENDENT KINASE-CATALYZED PHOSPHORYLATION by DISSANAYAKA M. MAHEEKA M. EMBOGAMA DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2017 MAJOR: CHEMISTRY (Biochemistry) Approved By: Advisor Date DEDICATION To my beloved mother, father, husband, daughter and sister. ii ACKNOWLEGEMENTS Many people have helped me during the past five years of earning my PhD. I would like to take this opportunity to convey my gratitude to them. First and foremost, I would like to thank my research supervisor Dr. Mary Kay Pflum for being the greatest mentor that I have met so far. -
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].