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Review
. 2020 Jun 9;11(6):635.
doi: 10.3390/genes11060635.

Location, Location, Location: The Role of Nuclear Positioning in the Repair of Collapsed Forks and Protection of Genome Stability

Jenna M Whalen  1 , Catherine H Freudenreich  1   2
Affiliations
Review

Location, Location, Location: The Role of Nuclear Positioning in the Repair of Collapsed Forks and Protection of Genome Stability

Jenna M Whalen et al. Genes (Basel). .

Abstract

Components of the nuclear pore complex (NPC) have been shown to play a crucial role in protecting against replication stress, and recovery from some types of stalled or collapsed replication forks requires movement of the DNA to the NPC in order to maintain genome stability. The role that nuclear positioning has on DNA repair has been investigated in several systems that inhibit normal replication. These include structure forming sequences (expanded CAG repeats), protein mediated stalls (replication fork barriers (RFBs)), stalls within the telomere sequence, and the use of drugs known to stall or collapse replication forks (HU + MMS or aphidicolin). Recently, the mechanism of relocation for collapsed replication forks to the NPC has been elucidated. Here, we will review the types of replication stress that relocate to the NPC, the current models for the mechanism of relocation, and the currently known protective effects of this movement.

Keywords: fork collapse; fork restart; nuclear pore complex; replication fork; replication fork barriers; sumoylation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Types of replication stress that cause fork collapse and lead to relocation to the nuclear pore complex (NPC). Upon replication stress, which can be caused by many different mechanisms, normal unperturbed replication forks can stall. Several mechanisms are shown in this model: structure-forming sequences (expanded CAG repeats), protein-mediated replication fork barriers (RFBs), telomere sequences, aphidicolin, and HU + MMS. After a replication fork stalls, it can turn into a fork collapse. This is marked by dissociation of the replisome and could possibly include breaks at the replication fork; the position of the various replisome components during fork collapse at these different barriers is not known and shown for diagrammatic purposes only. For simplicity, two structures that could result from a fork collapse are shown: a reversed replication fork and a broken replication fork, although we note there are other possible structures. For example, a reversed replication fork could be cleaved by endonucleases and, in turn, result in a broken replication fork with a different structure than the one shown here. Nonetheless, both reversed and broken replication forks can be substrates for resection, which is important to generate ssDNA that binds RPA. Repair proteins, sumoylated by E3 ligases (SUMO is indicated by the red circles), bind to the ssDNA and interact with the SIM domains in Slx5 (or its homologs). This stimulates relocation to the NPC through the interaction of Slx5 with the NPC protein Nup84 (or its homologs).
Figure 2
Figure 2
Model for events happening at the NPC to restart collapsed replication forks. Based on current data, the regulation of sumoylated proteins on the replication fork located at the NPC could occur by two mechanisms: (1) direct removal of SUMO by Ulp1 (which is bound to the NPC) and (2) STUbL-mediated ubiquitylation of sumoylated proteins (ubiquitin is indicated by yellow circles). It is important to note that both mechanisms could be happening at the same time at the collapsed replication fork. The STUbL-mediated ubiquitylation could either result in removal of the sumoylated proteins from the replication fork or it could target the sumoylated proteins to the proteasome for degradation or both. The removal and/or degradation of sumoylated proteins from the stalled replication fork is presumed to facilitate fork restart. Current data points to Rad51-dependent HR-mediated fork restart occurring while the collapsed replication fork is at the NPC; however, other outcomes at the NPC are possible, such as the resolution of HR intermediates or a converged fork. In this model, after the collapsed fork is restarted, it no longer remains at the NPC.
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