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Genes Dev. 2014 Nov 15;28(22):2450-63. doi: 10.1101/gad.248369.114. Epub 2014 Nov 3.

Nuclear position dictates DNA repair pathway choice.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch CEDEX, France; U964, Institut National de la Santé et de la Recherche Médicale (INSERM), 67404 Illkirch CEDEX, France; UMR7104, Centre National de Recherche Scientifique (CNRS), 67404 Illkirch CEDEX, France; Université de Strasbourg (UDS), 67404 Illkirch CEDEX, France;
2
Department of Pathology, Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.

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.

KEYWORDS:

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

PMID:
25366693
PMCID:
PMC4233239
DOI:
10.1101/gad.248369.114
[Indexed for MEDLINE]
Free PMC Article

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