SUMO-Based Regulation of Nuclear Positioning to Spatially Regulate Homologous Recombination Activities at Replication Stress Sites.

Kamila Schirmeisen,Sarah A E Lambert,Karol Kramarz

doi:10.3390/genes12122010

Abstract

DNA lesions have properties that allow them to escape their nuclear compartment to achieve DNA repair in another one. Recent studies uncovered that the replication fork, when its progression is impaired, exhibits increased mobility when changing nuclear positioning and anchors to nuclear pore complexes, where specific types of homologous recombination pathways take place. In yeast models, increasing evidence points out that nuclear positioning is regulated by small ubiquitin-like modifier (SUMO) metabolism, which is pivotal to maintaining genome integrity at sites of replication stress. Here, we review how SUMO-based pathways are instrumental to spatially segregate the subsequent steps of homologous recombination during replication fork restart. In particular, we discussed how routing towards nuclear pore complex anchorage allows distinct homologous recombination pathways to take place at halted replication forks.

Highlights

DNA lesions have properties that allow them to escape their nuclear compartment to achieve DNA repair in another one
The cancer risk of a given tissue is mathematically linked with the number of stem cell divisions, and cancer development and aggressiveness is associated with intrinsic replication stress [5,6]
We review how the spatially segregated small ubiquitin-like modifier (SUMO) metabolism in yeast nuclei regulates the distinct steps of homologous recombination (HR)-mediated fork restart and the relevance of this in human cells

Summary

Replication Stressed Forks and Homologous Recombination

In an average human life span, each individual copies approximatively 2 × 1016 m of DNA, representing 130,000 times the distance between the earth and the sun. HR repairs broken replication forks through a mechanism called break-induced replication (BIR) and ensures replication resumption at double strand break-free (DSB-free) arrested forks through template switching or a mechanism called recombination-dependent replication (RDR) [10,11,12]. Rad51-coated single-stranded DNA gaps formed through the well-controlled degradation of newly replicated strands [13,14,15,16] Both BIR and RDR are associated with mutagenic DNA synthesis, which distinguishes a restarted fork from a replication origin-born fork [12]. We review how the spatially segregated SUMO metabolism in yeast nuclei regulates the distinct steps of HR-mediated fork restart and the relevance of this in human cells

Replication Stress Sites Move to the Nuclear Periphery

SUMOylation in DNA Repair

NPCs Anchor DNA Lesions in a SUMO-Dependent Manner to Promote

Concluding Remarks