Nuclear position dictates DNA repair pathway choice (original) (raw)

1. Anastazja Grabarz1,2,3,4,7,
2. Katerina Tsouroula1,2,3,4,7,
3. Leonid Andronov1,2,3,4,
4. Audrey Furst1,2,3,4,
5. Tibor Pankotai1,2,3,4,
6. Vincent Heyer1,2,3,4,
7. Mélanie Rogier1,2,3,4,
8. Kathleen M. Attwood5,6,
9. Pascal Kessler1,2,3,4,
10. Graham Dellaire5,6,
11. Bruno Klaholz1,2,3,4,
12. Bernardo Reina-San-Martin1,2,3,4 and
13. Evi Soutoglou1,2,3,4
14. 1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch CEDEX, France;
15. 2U964, Institut National de la Santé et de la Recherche Médicale (INSERM), 67404 Illkirch CEDEX, France;
16. 3UMR7104, Centre National de Recherche Scientifique (CNRS), 67404 Illkirch CEDEX, France;
17. 4Université de Strasbourg (UDS), 67404 Illkirch CEDEX, France;
18. 5Department of Pathology,
19. 6Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
20. Corresponding author: evisou{at}igbmc.fr
21. ↵7 These two authors contributed equally to this work.

Abstract

Faithful DNA repair is essential to avoid chromosomal rearrangements and promote genome integrity. Nuclear organization has emerged as a key parameter in the formation of chromosomal translocations, yet little is known as to whether DNA repair can efficiently occur throughout the nucleus and whether it is affected by the location of the lesion. Here, we induce DNA double-strand breaks (DSBs) at different nuclear compartments and follow their fate. We demonstrate that DSBs induced at the nuclear membrane (but not at nuclear pores or nuclear interior) fail to rapidly activate the DNA damage response (DDR) and repair by homologous recombination (HR). Real-time and superresolution imaging reveal that DNA DSBs within lamina-associated domains do not migrate to more permissive environments for HR, like the nuclear pores or the nuclear interior, but instead are repaired in situ by alternative end-joining. Our results are consistent with a model in which nuclear position dictates the choice of DNA repair pathway, thus revealing a new level of regulation in DSB repair controlled by spatial organization of DNA within the nucleus.

• alternative end-joining
• DNA repair
• nuclear lamina
• nuclear organization

Footnotes

• Supplemental material is available for this article.

• Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.248369.114.
  Freely available online through the Genes & Development Open Access option.

• Received July 2, 2014.

• Accepted October 14, 2014.

• © 2014 Lemaître et al.; Published by Cold Spring Harbor Laboratory Press

This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.