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.