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Long-range chromatin organization and genome stability

English title Long-range chromatin organization and genome stability
Applicant Gasser Susan
Number 156936
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.01.2015 - 31.12.2017
Approved amount 850'370.00
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All Disciplines (2)

Discipline
Molecular Biology
Structural Research

Keywords (5)

chromatin structure; nuclear organization; DNA repair; genome stability; heterochromatin

Lay Summary (German)

Lead
Die Stabilität und der Expressionsstatus unseres Genoms ist nicht nur abhängig von der primären DNA-Sequenz, sondern auch von der 3 dimensionalen Anordnung der Chromosomen im Zellkern, der Positionierung und der Dynamik von Nukleosomen und dem Chromatinstatus. Die räumliche Anordnung des Genoms trägt in erheblichen Maße auch zu deren Stabilisierung bei. Sie wirkt als Katalysator, besonders wenn die Konzentration von essentiellen Faktoren limitiert ist und fördert die Vererbung von bestimmten Modifikationen des Chromatins über Zellteilungen hinweg.
Lay summary

Unser Ziel ist es zu verstehen nach welchen Mechanismen und mit welchen molekularen Bausteinen unser Genom im Zellkern angeordnet ist und welche der inter- und intrachromosomalen Interaktionen essentiell sind für die Funktion und Integrität des Genoms. Um die Beziehung von Struktur und Funktion besser zu verstehen benötigen wir die molekularen Werkzeuge der Genetik, der quantitativen Mikroskopie, in-vivo Biochemie, die Möglichkeit die Physiologie eines gesamten Organismus zu beobachten und ultimativ die Rekonstruktion von den einzelnen biochemischen Bestandteilen, welche Heterochromatin bilden, oder die Reparatur von Brüchen in der DNA vermitteln.

Sowohl die Stabilität unsere Genoms, als auch die Stabilität der Differenzierung von Zellen ist abhängig von der räumlichen Anordnung des Chromatins. Um einen größt möglichen Nutzen aus der Vielzahl an biologischen Werkzeugen in den verschieden Modelorganismen zu ziehen machen studieren wir sowohl die Hefe S. cerivisiae, als auch den Nematoden C. elegans. Hefen eigenen sich vor allen um die Mechanismen, die zur Erhaltung der Genom Stabilität unter verschiedenen Stressbedingungen beitragen zu studieren, während  C. elegans sich hervorragend dazu eignet die Rolle von Chromatin Organisation während der Entwicklung von verschieden Organen und Zelltypen aufzuklären. Beide Modelle erlauben uns das gezielte Einfügen von Mutationen in Genen von essentiellen Strukturproteinen, welche häufig die Veränderungen reflektieren, welche wir aus menschlichen Krankheitsbildern kennen. Damit haben wir die Möglichkeit eine Beziehung von Struktur und Funktion zu erhalten.

 

 

Direct link to Lay Summary Last update: 17.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Repressive Chromatin in Caenorhabditis elegans: Establishment, Composition, and Function.
Ahringer Julie, Gasser Susan M (2018), Repressive Chromatin in Caenorhabditis elegans: Establishment, Composition, and Function., in Genetics, 208(2), 491-511.
Chromatin and nucleosome dynamics in DNA damage and repair.
Hauer Michael H, Gasser Susan M (2017), Chromatin and nucleosome dynamics in DNA damage and repair., in Genes & development, 31(22), 2204-2221.
The Importance of Satellite Sequence Repression for Genome Stability.
Zeller Peter, Gasser Susan M (2017), The Importance of Satellite Sequence Repression for Genome Stability., in Cold Spring Harbor symposia on quantitative biology.
Chromatin modifiers and remodellers in DNA repair and signalling.
Jeggo Penny A, Downs Jessica A, Gasser Susan M (2017), Chromatin modifiers and remodellers in DNA repair and signalling., in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 372(1731), 20160279.
Structural Basis of Mec1-Ddc2-RPA Assembly and Activation on Single-Stranded DNA at Sites of Damage.
Deshpande Ishan, Seeber Andrew, Shimada Kenji, Keusch Jeremy J, Gut Heinz, Gasser Susan M (2017), Structural Basis of Mec1-Ddc2-RPA Assembly and Activation on Single-Stranded DNA at Sites of Damage., in Molecular cell, 68(2), 431-445.
The INO80 remodeller in transcription, replication and repair.
Poli Jérôme, Gasser Susan M, Papamichos-Chronakis Manolis (2017), The INO80 remodeller in transcription, replication and repair., in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 372(1731), 20160290.
Chromatin organization and dynamics in double-strand break repair.
Seeber Andrew, Gasser Susan M (2017), Chromatin organization and dynamics in double-strand break repair., in Current opinion in genetics & development, 43, 9-16.
Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates.
Hauer Michael H, Seeber Andrew, Singh Vijender, Thierry Raphael, Sack Ragna, Amitai Assaf, Kryzhanovska Mariya, Eglinger Jan, Holcman David, Owen-Hughes Tom, Gasser Susan M (2017), Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates., in Nature structural & molecular biology, 24(2), 99-107.
A game of musical chairs: Pro- and anti-resection factors compete for TOPBP1 binding after DNA damage.
Shimada Kenji, Gasser Susan M (2017), A game of musical chairs: Pro- and anti-resection factors compete for TOPBP1 binding after DNA damage., in The Journal of cell biology, 216(3), 535-537.
Visualization of Chromatin Decompaction and Break Site Extrusion as Predicted by Statistical Polymer Modeling of Single-Locus Trajectories
Amitai Assaf, Seeber Andrew, Gasser Susan M., Holcman David (2017), Visualization of Chromatin Decompaction and Break Site Extrusion as Predicted by Statistical Polymer Modeling of Single-Locus Trajectories, in Cell Reports, 18(5), 1200-1214.
Mechanism of chromatin segregation to the nuclear periphery in C. elegans embryos.
Gonzalez-Sandoval Adriana, Gasser Susan M (2016), Mechanism of chromatin segregation to the nuclear periphery in C. elegans embryos., in Worm, 5(3), 1190900-1190900.
Selfish DNA and Epigenetic Repression Revisited.
Gasser Susan M (2016), Selfish DNA and Epigenetic Repression Revisited., in Genetics, 204(3), 837-839.
RPA Mediates Recruitment of MRX to Forks and Double-Strand Breaks to hold Sister Chromatids Together
Seeber Andrew, Hegnauer Anna Maria, Hustedt Nicole, Deshpande Ishan, Poli Jérôme, Eglinger Jan, Pasero Philippe, Gut Heinz, Shinohara Miki, Hopfner Karl-Peter, Shimada Kenji, Gasser Susan M (2016), RPA Mediates Recruitment of MRX to Forks and Double-Strand Breaks to hold Sister Chromatids Together, in Molecular cell, 64(5), 951-966.
Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability.
Zeller Peter, Padeken Jan, van Schendel Robin, Kalck Veronique, Tijsterman Marcel, Gasser Susan M (2016), Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability., in Nature genetics, 48(11), 1385-1395.
SUMO wrestles breaks to the nuclear ring's edge.
Horigome Chihiro, Gasser Susan M (2016), SUMO wrestles breaks to the nuclear ring's edge., in Cell cycle (Georgetown, Tex.), 15(22), 3011-3013.
On TADs and LADs: Spatial Control Over Gene Expression
Gonzalez-Sandoval Adriana, Gasser Susan M. (2016), On TADs and LADs: Spatial Control Over Gene Expression, in TRENDS IN GENETICS, 32(8), 485-495.
Nuclear Architecture: Past and Future Tense
Gasser Susan M. (2016), Nuclear Architecture: Past and Future Tense, in TRENDS IN CELL BIOLOGY, 26(7), 473-475.
Spatial segregation of heterochromatin: Uncovering functionality in a multicellular organism.
Cabianca Daphne S, Gasser Susan M (2016), Spatial segregation of heterochromatin: Uncovering functionality in a multicellular organism., in Nucleus (Austin, Tex.), 7(3), 301-7.
PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL
Horigome Chihiro, Bustard Denise E., Marcomini Isabella, Delgoshaie Neda, Tsai-Pflugfelder Monika, Cobb Jennifer A., Gasser Susan M. (2016), PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL, in GENES & DEVELOPMENT, 30(8), 931-945.
The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation
Iwasaki Daichi, Hayashihara Kayoko, Shima Hiroki, Higashide Mika, Terasawa Masahiro, Gasser Susan M., Shinohara Miki (2016), The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation, in PLOS GENETICS, 12(3), 1005942.
Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man
Harr Jennifer C., Gonzalez-Sandoval Adriana, Gasser Susan M. (2016), Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man, in EMBO REPORTS, 17(2), 139-155.
Mec1, INO80, and the PAF1 complex cooperate to limit transcription replication conflicts through RNAPII removal during replication stress
Poli Jerome, Gerhold Christian-Benedikt, Tosi Alessandro, Hustedt Nicole, Seeber Andrew, Sack Ragna, Herzog Franz, Pasero Philippe, Shimada Kenji, Hopfner Karl-Peter, Gasser Susan M. (2016), Mec1, INO80, and the PAF1 complex cooperate to limit transcription replication conflicts through RNAPII removal during replication stress, in GENES & DEVELOPMENT, 30(3), 337-354.

Collaboration

Group / person Country
Types of collaboration
David Holcman (ENS Paris) France (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions The Future of Medicine International German-speaking Switzerland 2015

Awards

Title Year
Dr medicin honoris Causa, Charles University of Prague 2016
PhD honoris causa, University of Lausanne 2015

Associated projects

Number Title Start Funding scheme
176286 Roles of chromatin in genome stability 01.01.2018 Project funding (Div. I-III)
138334 Long-range Chromatin Organization and Genome Stability 01.01.2012 Project funding (Div. I-III)
141945 Mapping repair-relevant domains of the nuclear envelope by superresolution microscopy 01.08.2012 Sinergia

Abstract

Our research focuses on two key lines of research: mechanisms that ensure genomic stability during replication and repair of the genome in yeast, and the mechanisms that spatially organize and stabilize chromatin during C. elegans development. We use live microscopy techniques and Chromatin immunoprecipitation to analyse the long-range organization of chromatin in the nucleus, and we dissect the mechanisms and consequences of its perturbation in mutants. Recent work examines how the position and dynamics of chromatin loci affect the repair of double strand breaks or of endogenous damage that arises during replication. Our work on heterochromatin organization in C. elegans has been ground-breaking and has led to identification of a histone methylation event (H3K9me) as a necessary targeting signal for chromatin binding to the nuclear periphery. Juxtaposition to the nuclear envelope is known to affect DNA repair both in yeast and higher eukaryotes. We are pursuing the mechanism of positioning and the impact that either loss of localization and/or H3K9me has on genome stability in worms. In yeast we are examine the molecular crosstalk of checkpoint kinases, nucleosome remodelers, and the subdiffusive mobility of chromatin (and its ultimate subnuclear position) during various repair events. Our goal is to understand how local and long-range chromatin structures influence genome stability.
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