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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}fmi.ch

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