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Long-range Chromatin Organization and Genome Stability

English title Long-range Chromatin Organization and Genome Stability
Applicant Gasser Susan
Number 138334
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 01.01.2012 - 31.12.2014
Approved amount 697'869.00
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All Disciplines (3)

Discipline
Molecular Biology
Biophysics
Genetics

Lay Summary (English)

Lead
Lay summary

Long range chromatin movement and genome stability

Lay summary
The blueprint of every living cell is found in its DNA, yet just as important as the linear sequence of the genome, is its three-dimensional packaging.  Spatial organization of chromatin within our chromosomes is known to influence nearly every DNA-based transaction we know: transcription, replication, repair and recombination.  Not only the local compaction of DNA around histones and its subsequent folding into a 30nm fiber, but also the long-range juxtaposition of chromosomal domains near the nuclear lamina, nuclear pores, the nucleolus, or various subnuclear compartments of specialized activity, modulate events that are essential to maintain our genome intact.  Here we will explore the effect of the spatial organization of the genome on various forms of DNA repair. We will exploit genetically modifiable model organisms, combining  high resolution live imaging technologies to visualize sites of repair and nuclear landmarks, with genetic manipulation that allows us to alter the pathways that mediate repair. Using budding yeast we will examine the spatial dynamics of various types of damaged DNA and in the nematode, C. elegans, we will examine how repair is regulated by the packaging of DNA into heterochromatin or by its reorganization during differentiation into distinct tissues. By understanding the mechanisms used by cells to repair DNA lesions, we hope to have a significant impact on the  mutagenic processes that accompany aging and oncogenic transformation.

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Yeast PP4 Interacts with ATR Homolog Ddc2-Mec1 and Regulates Checkpoint Signaling.
Hustedt Nicole, Seeber Andrew, Sack Ragna, Tsai-Pflugfelder Monika, Bhullar Bhupinder, Vlaming Hanneke, van Leeuwen Fred, Guénolé Aude, van Attikum Haico, Srivas Rohith, Ideker Trey, Shimada Kenji, Gasser Susan M (2015), Yeast PP4 Interacts with ATR Homolog Ddc2-Mec1 and Regulates Checkpoint Signaling., in Molecular cell, 57(2), 273-89.
INO80 and SWR complexes: relating structure to function in chromatin remodeling
Gerhold Christian B., Gasser Susan M. (2014), INO80 and SWR complexes: relating structure to function in chromatin remodeling, in TRENDS IN CELL BIOLOGY, 24(11), 619-631.
INO80-C and SWR-C: Guardians of the Genome.
Gerhold Christian-Benedikt, Hauer Michael H, Gasser Susan M (2014), INO80-C and SWR-C: Guardians of the Genome., in Journal of molecular biology, pii: S002.
Remodelers move chromatin in response to DNA damage
Seeber Andrew, Dion Vincent, Gasser Susan M. (2014), Remodelers move chromatin in response to DNA damage, in CELL CYCLE, 13(6), 877-878.
Remodelers move chromatin in response to DNA damage.
Seeber Andrew, Dion Vincent, Gasser Susan M (2014), Remodelers move chromatin in response to DNA damage., in Cell cycle (Georgetown, Tex.), 13(6), 877-8.
SWR1 and INO80 Chromatin Remodelers Contribute to DNA Double-Strand Break Perinuclear Anchorage Site Choice
Horigome Chihiro, Oma Yukako, Konishi Tatsunori, Schmid Roger, Marcomini Isabella, Hauer Michael H., Dion Vincent, Harata Masahiko, Gasser Susan M. (2014), SWR1 and INO80 Chromatin Remodelers Contribute to DNA Double-Strand Break Perinuclear Anchorage Site Choice, in MOLECULAR CELL, 55(4), 626-639.
TORC2-a new player in genome stability
Weisman Ronit, Cohen Adiel, Gasser Susan M. (2014), TORC2-a new player in genome stability, in EMBO MOLECULAR MEDICINE, 6(8), 995-1002.
A Rad53 Independent Function of Rad9 Becomes Crucial for Genome Maintenance in the Absence of the RecQ Helicase Sgs1
Nielsen Ida, Bentsen Iben Bach, Andersen Anni H., Gasser Susan M., Bjergbaek Lotte (2013), A Rad53 Independent Function of Rad9 Becomes Crucial for Genome Maintenance in the Absence of the RecQ Helicase Sgs1, in PLOS ONE, 8(11), e810.
Checkpoint kinases and the INO80 nucleosome remodeling complex enhance global chromatin mobility in response to DNA damage.
Seeber Andrew, Dion Vincent, Gasser Susan M (2013), Checkpoint kinases and the INO80 nucleosome remodeling complex enhance global chromatin mobility in response to DNA damage., in Genes & development, 27(18), 1999-2008.
Chromatin movement in the maintenance of genome stability
Dion V, Gasser SM (2013), Chromatin movement in the maintenance of genome stability, in Cell, 152, 1255-1364.
Cohesin and the nucleolus constrain the mobility of spontaneous repair foci.
Dion Vincent, Kalck Véronique, Seeber Andrew, Schleker Thomas, Gasser Susan M (2013), Cohesin and the nucleolus constrain the mobility of spontaneous repair foci., in EMBO reports, 14(11), 984-91.
Dimerization of Sir3 via its C-terminal winged helix domain is essential for yeast heterochromatin formation.
Oppikofer Mariano, Kueng Stephanie, Keusch Jeremy J, Hassler Markus, Ladurner Andreas G, Gut Heinz, Gasser Susan M (2013), Dimerization of Sir3 via its C-terminal winged helix domain is essential for yeast heterochromatin formation., in The EMBO journal, 32(3), 437-49.
Epigenetics in Saccharomyces cerevisiae.
Grunstein Michael, Gasser Susan M (2013), Epigenetics in Saccharomyces cerevisiae., in Cold Spring Harbor perspectives in biology, 5(7), pii: a0174.
Mechanisms of heterochromatin subnuclear localization
Towbin Benjamin D., Gonzalez-Sandoval Adriana, Gasser Susan M. (2013), Mechanisms of heterochromatin subnuclear localization, in TRENDS IN BIOCHEMICAL SCIENCES, 38(7), 356-363.
Nucleosome remodelers in double-strand break repair.
Seeber Andrew, Hauer Michael, Gasser Susan M (2013), Nucleosome remodelers in double-strand break repair., in Current opinion in genetics & development, 23(2), 174-84.
Open questions: epigenetics and the role of heterochromatin in development.
Gasser Susan M (2013), Open questions: epigenetics and the role of heterochromatin in development., in BMC biology, 11, 21-21.
Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans.
Rohner Sabine, Kalck Veronique, Wang Xuefei, Ikegami Kohta, Lieb Jason D, Gasser Susan M, Meister Peter (2013), Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans., in The Journal of cell biology, 200(5), 589-604.
Replication checkpoint: tuning and coordination of replication forks in s phase.
Hustedt Nicole, Gasser Susan M, Shimada Kenji (2013), Replication checkpoint: tuning and coordination of replication forks in s phase., in Genes, 4(3), 388-434.
SIR proteins and the assembly of silent chromatin in budding yeast.
Kueng Stephanie, Oppikofer Mariano, Gasser Susan M (2013), SIR proteins and the assembly of silent chromatin in budding yeast., in Annual review of genetics, 47, 275-306.
SIR-nucleosome interactions: Structure-function relationships in yeast silent chromatin
Oppikofer Mariano, Kueng Stephanie, Gasser Susan M. (2013), SIR-nucleosome interactions: Structure-function relationships in yeast silent chromatin, in GENE, 527(1), 10-25.
The formation and sequestration of heterochromatin during development Delivered on 7 September 2012 at the 37th FEBS Congress in Sevilla, Spain
Gonzalez-Sandoval Adriana, Towbin Benjamin D., Gasser Susan M. (2013), The formation and sequestration of heterochromatin during development Delivered on 7 September 2012 at the 37th FEBS Congress in Sevilla, Spain, in FEBS JOURNAL, 280(14), 3212-3219.
The shelterin protein POT-1 anchors Caenorhabditis elegans telomeres through SUN-1 at the nuclear periphery.
Ferreira Helder C, Towbin Benjamin D, Jegou Thibaud, Gasser Susan M (2013), The shelterin protein POT-1 anchors Caenorhabditis elegans telomeres through SUN-1 at the nuclear periphery., in The Journal of cell biology, 203(5), 727-35.
TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks.
Shimada Kenji, Filipuzzi Ireos, Stahl Michael, Helliwell Stephen B, Studer Christian, Hoepfner Dominic, Seeber Andrew, Loewith Robbie, Movva N Rao, Gasser Susan M (2013), TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks., in Molecular cell, 51(6), 829-39.
An N-terminal acidic region of Sgs1 interacts with Rpa70 and recruits Rad53 kinase to stalled forks
Hegnauer Anna Maria, Hustedt Nicole, Shimada Kenji, Pike Brietta L., Vogel Markus, Amsler Philipp, Rubin Seth M., van Leeuwen Fred, Guenole Aude, van Attikum Haico, Thomae Nicolas H., Gasser Susan M. (2012), An N-terminal acidic region of Sgs1 interacts with Rpa70 and recruits Rad53 kinase to stalled forks, in EMBO JOURNAL, 31(18), 3768-3783.
Increased dynamics at double strand breaks requires Mec1, Rad9 and the homologous recombination machinery
Dion V, Kalck V, Horigome C, Towbin B, Gasser S.M (2012), Increased dynamics at double strand breaks requires Mec1, Rad9 and the homologous recombination machinery, in Nature Cell Biol, 14(5), 502-509.
Nucleosome remodeler-induced chromatin dynamics enhance repair by homologous recombination
Neumann F.R, Dion V, Gehlen L., Taddei A, Tsai-Pflugfelder M., Gasser S.M. (2012), Nucleosome remodeler-induced chromatin dynamics enhance repair by homologous recombination, in Genes & Development, 26(4), 369-383.
Regulating Repression: Roles for the Sir4 N-Terminus in Linker DNA Protection and Stabilization of Epigenetic States
Kueng S, Tsai-Pflugfelder M, Oppikofer M., Sack R, Ferreira. H.C, Gasser S.M (2012), Regulating Repression: Roles for the Sir4 N-Terminus in Linker DNA Protection and Stabilization of Epigenetic States, in PLOS Genetics, 8 (5), e1002727.
Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery.
Towbin Benjamin D, González-Aguilera Cristina, Sack Ragna, Gaidatzis Dimos, Kalck Véronique, Meister Peter, Askjaer Peter, Gasser Susan M (2012), Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery., in Cell, 150(5), 934-47.
Structure and Function in the Budding Yeast Nucleus
Taddei Angela, Gasser Susan M. (2012), Structure and Function in the Budding Yeast Nucleus, in GENETICS, 192(1), 107-129.
Structure and function in the budding yeast nucleus.
Taddei Angela, Gasser Susan M (2012), Structure and function in the budding yeast nucleus., in Genetics, 192(1), 107-29.

Collaboration

Group / person Country
Types of collaboration
HOlcman, Ecole Normale superieure France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Shinohara, Osaka University Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Harata, Tohoku University Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Grunbaum, Hebrew Universityof Jerusalem Israel (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gordon conference Talk given at a conference DNA dynamics in DNA repair 08.07.2014 HOngkong, Hongkong Horigome Chihiro; Gasser Susan;


Self-organised

Title Date Place
Targeting the Kinome III 26.09.2014 Basel, Switzerland
Arolla Workshop of Cell and Developmental Systems 21.08.2012 Arolla, Switzerland
Women in Science day 18.04.2012 Basel, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Dies academicus, U of Basel German-speaking Switzerland 2013

Awards

Title Year
Doctorat Honoris causa, University of Lausanne 2014
Weizmann Institute Women in Science award (Israel) 2013
FEBS/EMBO Women in Science award 2012 2012
Member of the EC President’s Science and Technology Advisory Council 2012

Patents

Title Date Number Inventor Owner
Combining DNA-damaging agents and modulators of actin polymerization for the treatment of cancer 03.05.2013 55012 (Gasser/Movva)

Associated projects

Number Title Start Funding scheme
141945 Mapping repair-relevant domains of the nuclear envelope by superresolution microscopy 01.08.2012 Sinergia
156936 Long-range chromatin organization and genome stability 01.01.2015 Project funding (Div. I-III)

Abstract

Nuclear organization is known to influence transcription, but has only recently been shown to be relevant for DNA repair. We hypothesize that nuclear subcompartments influence repair efficiency as well as repair pathway choice. We propose to test this with a combined imaging and genetic approach that examines chromatin movement during the repair process. We will examine the role of factors that regulate both movement and DNA repair in vivo, namely chromatin remodelers and SUMO modification. Work in yeast allows us to perform detailed functional studies describing the core mechanisms of damage relocalization. We then expand our studies to C. elegans, where we will examine how this is regulated by heterochromatin context and differentiation. We will analyse whether chromatin context, such as developmentally or repeat-induced heterochromatin, alters either the rate or outcome of repair, and whether the importance of chromatin remodeling or damage relocation increases when damage occurs in a heterochromatic context. The use of model organisms allows us to screen for novel chromatin remodeling / modulatory factors important for double strand break repair.
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