title: DSB (Im)mobility and DNA repair compartmentalization in mammalian cells.
abstract: Chromosomal translocations are considered as causal in approximately 20% of cancers. Therefore, understanding their mechanisms of formation is crucial in the prevention of carcinogenesis. The first step of translocation formation is the concomitant occurrence of double-strand DNA breaks (DSBs) in two different chromosomes. DSBs can be repaired by different repair mechanisms, including error-free homologous recombination (HR), potentially error-prone non-homologous end joining (NHEJ) and the highly mutagenic alternative end joining (alt-EJ) pathways. Regulation of DNA repair pathway choice is crucial to avoid genomic instability. In yeast, DSBs are mobile and can scan the entire nucleus to be repaired in specialized DNA repair centers or if they are persistent, in order to associate with the nuclear pores or the nuclear envelope where they can be repaired by specialized repair pathways. DSB mobility is limited in mammals; therefore, raising the question of whether the position at which a DSB occurs influences its repair. Here, we review the recent literature addressing this question. We first present the reports describing the extent of DSB mobility in mammalian cells. In a second part, we discuss the consequences of non-random gene positioning on chromosomal translocations formation. In the third part, we discuss the mobility of heterochromatic DSBs in light of our recent data on DSB repair at the nuclear lamina, and finally, we show that DSB repair compartmentalization at the nuclear periphery is conserved from yeast to mammals, further pointing to a role for gene positioning in the outcome of DSB repair. When regarded as a whole, the different studies reviewed here demonstrate the importance of nuclear architecture on DSB repair and reveal gene positioning as an important parameter in the study of tumorigenesis.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, CEDEX, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, 67404, Illkirch, CEDEX, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Lemaître
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, CEDEX, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Centre National de Recherche Scientifique, UMR7104, Illkirch, France; Université de Strasbourg, 67404, Illkirch, CEDEX, France. Electronic address: evisou@igbmc.fr.
authors.forename: Evi
authors.initials: E
authors.lastname: Soutoglou
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D014178:Translocation, Genetic
chemical_list: D002843:Chromatin
keywords: DNA damage; chromatin; nuclear organization