Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 322 (5901): 597-602

Copyright © 2008 by the American Association for the Advancement of Science

Functional Targeting of DNA Damage to a Nuclear Pore-Associated SUMO-Dependent Ubiquitin Ligase

Shigeki Nagai,1,2* Karine Dubrana,2*{dagger} Monika Tsai-Pflugfelder,1 Marta B. Davidson,3 Tania M. Roberts,3 Grant W. Brown,3 Elisa Varela,1 Florence Hediger,2 Susan M. Gasser,1,2{ddagger} Nevan J. Krogan4

Abstract: Recent findings suggest important roles for nuclear organization in gene expression. In contrast, little is known about how nuclear organization contributes to genome stability. Epistasis analysis (E-MAP) using DNA repair factors in yeast indicated a functional relationship between a nuclear pore subcomplex and Slx5/Slx8, a small ubiquitin-like modifier (SUMO)–dependent ubiquitin ligase, which we show physically interact. Real-time imaging and chromatin immunoprecipitation confirmed stable recruitment of damaged DNA to nuclear pores. Relocation required the Nup84 complex and Mec1/Tel1 kinases. Spontaneous gene conversion can be enhanced in a Slx8- and Nup84-dependent manner by tethering donor sites at the nuclear periphery. This suggests that strand breaks are shunted to nuclear pores for a repair pathway controlled by a conserved SUMO-dependent E3 ligase.

1 Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
2 Department of Molecular Biology and National Center of Competence in Research Frontiers in Genetics, 30 Quai Ernest Ansermet, 1211 Geneva, Switzerland.
3 Department of Biochemistry, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
4 Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, University of California, San Francisco, 1700 Fourth Street, San Francisco, CA 94158, USA.

* These authors contributed equally to this work.

{dagger} Present address: UMR218, Institut Curie/Section de Recherche, 26 Rue d'Ulm, 75231 Paris, and Institut de Radiobiologie Cellulaire et Moléculaire, CEA, 92265 Fontenay aux Roses, France.

{ddagger} To whom correspondence should be addressed. E-mail: susan.gasser{at}

Differential network biology.
T. Ideker and N. J. Krogan (2014)
Mol Syst Biol 8, 565
   Abstract »    Full Text »    PDF »
A SUMO-targeted ubiquitin ligase is involved in the degradation of the nuclear pool of the SUMO E3 ligase Siz1.
J. W. Westerbeck, N. Pasupala, M. Guillotte, E. Szymanski, B. C. Matson, C. Esteban, and O. Kerscher (2014)
Mol. Biol. Cell 25, 1-16
   Abstract »    Full Text »    PDF »
Identification of Arabidopsis SUMO-interacting proteins that regulate chromatin activity and developmental transitions.
N. Elrouby, M. V. Bonequi, A. Porri, and G. Coupland (2013)
PNAS 110, 19956-19961
   Abstract »    Full Text »    PDF »
Activation of the SUMO modification system is required for the accumulation of RAD51 at sites of DNA damage.
H. Shima, H. Suzuki, J. Sun, K. Kono, L. Shi, A. Kinomura, Y. Horikoshi, T. Ikura, M. Ikura, R. Kanaar, et al. (2013)
J. Cell Sci. 126, 5284-5292
   Abstract »    Full Text »    PDF »
Cohesin and the nucleolus constrain the mobility of spontaneous repair foci.
V. Dion, V. Kalck, A. Seeber, T. Schleker, and S. M. Gasser (2013)
EMBO Rep. 14, 984-991
   Abstract »    Full Text »    PDF »
Repair of Strand Breaks by Homologous Recombination.
M. Jasin and R. Rothstein (2013)
Cold Spring Harb Perspect Biol 5, a012740
   Abstract »    Full Text »    PDF »
RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells.
R. L. Ragland, S. Patel, R. S. Rivard, K. Smith, A. A. Peters, A.-K. Bielinsky, and E. J. Brown (2013)
Genes & Dev. 27, 2259-2273
   Abstract »    Full Text »    PDF »
DNA Damage Response: Three Levels of DNA Repair Regulation.
B. M. Sirbu and D. Cortez (2013)
Cold Spring Harb Perspect Biol 5, a012724
   Abstract »    Full Text »    PDF »
Rap1 relocalization contributes to the chromatin-mediated gene expression profile and pace of cell senescence.
J. M. Platt, P. Ryvkin, J. J. Wanat, G. Donahue, M. D. Ricketts, S. P. Barrett, H. J. Waters, S. Song, A. Chavez, K. O. Abdallah, et al. (2013)
Genes & Dev. 27, 1406-1420
   Abstract »    Full Text »    PDF »
Long-range heterochromatin association is mediated by silencing and double-strand DNA break repair proteins.
J. G. Kirkland and R. T. Kamakaka (2013)
J. Cell Biol. 201, 809-826
   Abstract »    Full Text »    PDF »
How Broken DNA Finds Its Template for Repair: A Computational Approach.
L. R. Gehlen, S. M. Gasser, and V. Dion (2013)
Prog. Theor. Phys. Supplement 191, 20-29
   Abstract »    PDF »
End-joining inhibition at telomeres requires the translocase and polySUMO-dependent ubiquitin ligase Uls1.
R. Lescasse, S. Pobiega, I. Callebaut, and S. Marcand (2013)
EMBO J. 32, 805-815
   Abstract »    Full Text »    PDF »
Dynamics of the DNA damage response: insights from live-cell imaging.
K. Karanam, A. Loewer, and G. Lahav (2013)
Briefings in Functional Genomics 12, 109-117
   Abstract »    Full Text »    PDF »
Bioinformatic identification of genes suppressing genome instability.
C. D. Putnam, S. R. Allen-Soltero, S. L. Martinez, J. E. Chan, T. K. Hayes, and R. D. Kolodner (2012)
PNAS 109, E3251-E3259
   Abstract »    Full Text »    PDF »
Structure and Function in the Budding Yeast Nucleus.
A. Taddei and S. M. Gasser (2012)
Genetics 192, 107-129
   Abstract »    Full Text »    PDF »
Leveraging input and output structures for joint mapping of epistatic and marginal eQTLs.
S. Lee and E. P. Xing (2012)
Bioinformatics 28, i137-i146
   Abstract »    Full Text »    PDF »
Gold nanoparticles as a platform for creating a multivalent poly-SUMO chain inhibitor that also augments ionizing radiation.
Y.-J. Li, A. L. Perkins, Y. Su, Y. Ma, L. Colson, D. A. Horne, and Y. Chen (2012)
PNAS 109, 4092-4097
   Abstract »    Full Text »    PDF »
The Yeast Nuclear Pore Complex and Transport Through It.
J. D. Aitchison and M. P. Rout (2012)
Genetics 190, 855-883
   Abstract »    Full Text »    PDF »
Targeted INO80 enhances subnuclear chromatin movement and ectopic homologous recombination.
F. R. Neumann, V. Dion, L. R. Gehlen, M. Tsai-Pflugfelder, R. Schmid, A. Taddei, and S. M. Gasser (2012)
Genes & Dev. 26, 369-383
   Abstract »    Full Text »    PDF »
The SUMO-specific isopeptidase SENP2 associates dynamically with nuclear pore complexes through interactions with karyopherins and the Nup107-160 nucleoporin subcomplex.
J. Goeres, P.-K. Chan, D. Mukhopadhyay, H. Zhang, B. Raught, and M. J. Matunis (2011)
Mol. Biol. Cell 22, 4868-4882
   Abstract »    Full Text »    PDF »
The Swi2-Snf2-like protein Uls1 is involved in replication stress response.
M. Cal-Bakowska, I. Litwin, T. Bocer, R. Wysocki, and D. Dziadkowiec (2011)
Nucleic Acids Res. 39, 8765-8777
   Abstract »    Full Text »    PDF »
Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression.
M. Abed, K. C. Barry, D. Kenyagin, B. Koltun, T. M. Phippen, J. J. Delrow, S. M. Parkhurst, and A. Orian (2011)
EMBO J. 30, 1289-1301
   Abstract »    Full Text »    PDF »
Genetic Analysis Implicates the Set3/Hos2 Histone Deacetylase in the Deposition and Remodeling of Nucleosomes Containing H2A.Z.
M. Hang and M. M. Smith (2011)
Genetics 187, 1053-1066
   Abstract »    Full Text »    PDF »
Principles of chromosomal organization: lessons from yeast.
C. Zimmer and E. Fabre (2011)
J. Cell Biol. 192, 723-733
   Abstract »    Full Text »    PDF »
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.
S. E. Polo and S. P. Jackson (2011)
Genes & Dev. 25, 409-433
   Abstract »    Full Text »    PDF »
Analysis of DNA double-strand break response and chromatin structure in mitosis using laser microirradiation.
V. Gomez-Godinez, T. Wu, A. J. Sherman, C. S. Lee, L.-H. Liaw, Y. Zhongsheng, K. Yokomori, and M. W. Berns (2010)
Nucleic Acids Res. 38, e202
   Abstract »    Full Text »    PDF »
Cdk Phosphorylation of a Nucleoporin Controls Localization of Active Genes through the Cell Cycle.
D. Garvey Brickner and J. H. Brickner (2010)
Mol. Biol. Cell 21, 3421-3432
   Abstract »    Full Text »    PDF »
The Budding Yeast Nucleus.
A. Taddei, H. Schober, and S. M. Gasser (2010)
Cold Spring Harb Perspect Biol 2, a000612
   Abstract »    Full Text »    PDF »
Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction.
M. L. Kozak, A. Chavez, W. Dang, S. L. Berger, A. Ashok, X. Guo, and F. B. Johnson (2010)
EMBO J. 29, 158-170
   Abstract »    Full Text »    PDF »
Structure of a trimeric nucleoporin complex reveals alternate oligomerization states.
V. Nagy, K.-C. Hsia, E. W. Debler, M. Kampmann, A. M. Davenport, G. Blobel, and A. Hoelz (2009)
PNAS 106, 17693-17698
   Abstract »    Full Text »    PDF »
Transportin Regulates Major Mitotic Assembly Events: From Spindle to Nuclear Pore Assembly.
C. K. Lau, V. A. Delmar, R. C. Chan, Q. Phung, C. Bernis, B. Fichtman, B. A. Rasala, and D. J. Forbes (2009)
Mol. Biol. Cell 20, 4043-4058
   Abstract »    Full Text »    PDF »
Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.
I. Gonzalez-Suarez, A. B. Redwood, S. M. Perkins, B. Vermolen, D. Lichtensztejin, D. A. Grotsky, L. Morgado-Palacin, E. J. Gapud, B. P. Sleckman, T. Sullivan, et al. (2009)
EMBO J. 28, 2414-2427
   Abstract »    Full Text »    PDF »
Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF.
A. Ottaviani, C. Schluth-Bolard, S. Rival-Gervier, A. Boussouar, D. Rondier, A. M. Foerster, J. Morere, S. Bauwens, S. Gazzo, E. Callet-Bauchu, et al. (2009)
EMBO J. 28, 2428-2436
   Abstract »    Full Text »    PDF »
Life on the edge: telomeres and persistent DNA breaks converge at the nuclear periphery.
M. R. Gartenberg (2009)
Genes & Dev. 23, 1027-1031
   Abstract »    Full Text »    PDF »
The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence.
R. Geisberger, C. Rada, and M. S. Neuberger (2009)
PNAS 106, 6736-6741
   Abstract »    Full Text »    PDF »
Mechanisms that regulate localization of a DNA double-strand break to the nuclear periphery.
P. Oza, S. L. Jaspersen, A. Miele, J. Dekker, and C. L. Peterson (2009)
Genes & Dev. 23, 912-927
   Abstract »    Full Text »    PDF »
Yeast telomerase and the SUN domain protein Mps3 anchor telomeres and repress subtelomeric recombination.
H. Schober, H. Ferreira, V. Kalck, L. R. Gehlen, and S. M. Gasser (2009)
Genes & Dev. 23, 928-938
   Abstract »    Full Text »    PDF »
The Saccharomyces cerevisiae Esc2 and Smc5-6 Proteins Promote Sister Chromatid Junction-mediated Intra-S Repair.
J. Sollier, R. Driscoll, F. Castellucci, M. Foiani, S. P. Jackson, and D. Branzei (2009)
Mol. Biol. Cell 20, 1671-1682
   Abstract »    Full Text »    PDF »
Regulation of Nuclear Positioning and Dynamics of the Silent Mating Type Loci by the Yeast Ku70/Ku80 Complex.
K. Bystricky, H. Van Attikum, M.-D. Montiel, V. Dion, L. Gehlen, and S. M. Gasser (2009)
Mol. Cell. Biol. 29, 835-848
   Abstract »    Full Text »    PDF »
Deficient SUMO Attachment to Flp Recombinase Leads to Homologous Recombination-dependent Hyperamplification of the Yeast 2 {micro}m Circle Plasmid.
L. Xiong, X. L. Chen, H. R. Silver, N. T. Ahmed, and E. S. Johnson (2009)
Mol. Biol. Cell 20, 1241-1251
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882