Repair by a molecular DNA ambulance

Most of the genome of a eukaryotic cell is located in its nucleus, which is a ball-like entity defined by a membrane bilayer known as the nuclear envelope. Constitutive physical interactions between certain chromosomal domains and inner nuclear membrane proteins can directly promote genome stability and cellular lifespan by preventing aberrant DNA recombination events [1, 2]. In addition, DNA loci experiencing DNA double-strand breaks (DSBs) exhibit increased interactions with nuclear pore complexes at the nuclear envelope and this is thought to contribute to DNA repair [3, 4, 5]. That a change in the subnuclear positioning of a damaged DNA locus may contribute to its repair has been observed in various organisms including yeast and human [3-6]. DSBs changing location may be escaping subnuclear neighbourhoods that are not conducive to repair, moving to specialized regions that directly promote repair, and/ or searching for homologous DNA sequences to serve as donors for repair. How DSBs move within the eukaryotic nucleus and what DNA repair pathways are engaged via this movement is unclear. We recently utilized the power of yeast genetics in order to address these questions. We assessed the ability of cells to survive DSBs precisely induced at different locations across the genome and analyzed the chromosomes of cells surviving the DNA break [7]. This analysis revealed that DSBs close to linear chromosome ends, or telomeres, are preferentially repaired via an error-prone type of homologous recombination called break-induced replication (BIR) [7]. Essential to this repair process were inner nuclear membrane proteins that typically work to tether telomeres to the nuclear envelope. Also critical to DSB survival was a particular nuclear pore complex. Abrogating the inner nuclear membrane proteins but not the nuclear pore complex released telomeres from the nuclear envelope in the absence of DNA damage. This is consistent with the fact that yeast telomeres are typically arranged in a handful of clusters abutting the inner nuclear membrane but away from nuclear pore regions. Interestingly however, genetic and molecular biology experiments revealed that DSB induction greatly increases physical interactions between the damaged chromosome ends and nuclear pore complexes. This increased interaction is dependent on perinuclear telomere tethers as well as a kinesin motor protein complex called Kinesin-14. This BIR-dependent DNA repair process was promoted via disruption of chromatin silencing but repressed upon abrogation of chromatin remodelling, DNA damage responses, or microtubule stability. Interestingly, artificially targeting DNA loci to nuclear pore complexes via …