Recombinational DNA repair is regulated by compartmentalization of DNA lesions at the nuclear pore complex

Abstract

The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of "difficult to repair" lesions such as double-strand breaks without a repair template and eroded telomeres in telomerase-deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure-forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus to the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC-facilitated repair.

PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL

“…Breaks that are difficult to repair due to a lack of homologous donor sequences or conditions that impair end-to-end ligation must be repaired by alternative pathways, which include imprecise or microhomology-mediated end-joining or break-induced replication (BIR) (for review, see Ceccaldi et al 2016). Repair pathway choice is influenced by both the cell cycle (which in turn impacts resection at the break site) and the chromatin context of the damage (Nagai et al 2010;Geli and Lisby 2015).…”

“…Compartmentation can either stem from the chromatin context of the damage (Therizols et al 2006;Khadaroo et al 2009;Agmon et al 2013) or arise through recruitment of the damage to specific subnuclear sites (for review, see Nagai et al 2010;Geli and Lisby 2015). For example, DSBs in the repetitive ribosomal DNA locus of yeast or in heterochromatic satellite repeats of flies and mammalian cells shift away from the repetitive sequence domain prior to repair by HR (Torres-Rosell et al 2007;Chiolo et al 2011;Lemaître et al 2014).…”

“…Within 2 h of their induction, such persistent DNA breaks accumulate at the nuclear envelope (NE) (Nagai et al 2008). Similarly, collapsed replication forks and those stalled at expanded triplet repeats (Su et al 2015) were shown to shift to nuclear pores, as do uncapped telomeres that arise from telomere erosion in telomerasedeficient cells (for review, see Geli and Lisby 2015). It is noteworthy that the repair of these three types of damage requires mechanisms other than precise end-joining or canonical HR.…”

“…Indeed, sites of active HR, visualized as Rad52 foci, are found in the nuclear interior and are specifically excluded from the NE and the nucleolus (Bystricky et al 2009;. Besides conferring sensitivity to exogenous agents (Bennett et al 2001), nuclear pore mutants showed impaired replication fork restart (for review, see Bukata et al 2013;Geli and Lisby 2015) and have recently been implicated in the repair of subtelomeric DSBs by strand invasion events . In human cells, components in the Nup84 complex were found to suppress elevated levels of H2AX phosphorylation in cells exposed to aphidicolin (Paulsen et al 2009), and, in flies, the loss of the corresponding complex enhanced the appearance of damage foci provoked by ionizing irradiation (Ryu et al 2015).…”

Relocalization of DNA lesions to the nuclear pore complex

“…In the last decade, it has been appreciated that some of these types of persistent lesions relocate to the nuclear periphery, and this relocation appears to play an important role in rescuing the repair process and facilitating its completion (see Lisby et al. 2010; Nagai, Heun and Gasser 2010; Nagai, Davoodi and Gasser 2011; Geli and Lisby 2015 for other recent reviews). In this review, we will provide a brief summary of the current state of the field, focusing on the types of lesions known to relocate to the nuclear pore in Saccharomyces cerevisiae , and the possible roles of this event in facilitating or regulating DNA repair and fork restart.…”