Abstract
Complete and faithful duplication of its entire genetic material is one of the essential prerequisites for a proliferating cell to maintain genome stability. Yet, during replication DNA is particularly vulnerable to insults. On the one hand, lesions in replicating DNA frequently cause a stalling of the replication machinery, as most DNA polymerases cannot cope with defective templates. This situation is aggravated by the fact that strand separation in preparation for DNA synthesis prevents common repair mechanisms relying on strand complementarity, such as base and nucleotide excision repair, from working properly. On the other hand, the replication process itself subjects the DNA to a series of hazardous transformations, ranging from the exposure of single-stranded DNA to topological contortions and the generation of nicks and fragments, which all bear the risk of inducing genomic instability. Dealing with these problems requires rapid and flexible responses, for which posttranslational protein modifications that act independently of protein synthesis are particularly well suited. Hence, it is not surprising that members of the ubiquitin family, particularly ubiquitin itself and SUMO, feature prominently in controlling many of the defensive and restorative measures involved in the protection of DNA during replication. In this review we will discuss the contributions of ubiquitin and SUMO to genome maintenance specifically as they relate to DNA replication. We will consider cases where the modifiers act during regular, i.e., unperturbed stages of replication, such as initiation, fork progression, and termination, but also give an account of their functions in dealing with lesions, replication stalling and fork collapse.
Highlights
DNA replication in eukaryotes is a multi-step process that is tightly coupled to both cell cycle progression and the DNA damage response (Leman and Noguchi, 2013; Siddiqui et al, 2013; Berti and Vindigni, 2016)
It has been observed that cells deficient in components of the Nup84 nuclear pore subcomplex are hypersensitive to DNA-damaging agents (Bennett et al, 2001; Loeillet et al, 2005; Therizols et al, 2006) and accumulate spontaneous recombination foci in S and G2 phase (Loeillet et al, 2005; Palancade et al, 2007; Nagai et al, 2008). Mutations in both Nup84 and the homologous recombination (HR) pathway are synthetically lethal (Loeillet et al, 2005). These findings suggest that the nuclear pore complex (NPC) plays a role in replication during both unperturbed and stress conditions, and HR-based mechanisms to resolve fork problems become essential when NPC function is compromised
When compared to replication initiation, which is largely coupled to cell cycle regulatory events, replication fork progression appears to be an extremely delicate condition in which numerous modulating modifications are needed to fine-tune the activity of various components or stabilize weakly associated complexes in order to maintain fork integrity
Summary
DNA replication in eukaryotes is a multi-step process that is tightly coupled to both cell cycle progression and the DNA damage response (Leman and Noguchi, 2013; Siddiqui et al, 2013; Berti and Vindigni, 2016). Upon encounter of replication-stalling DNA lesions, damage processing is channeled into a bypass pathway that depends on PCNA ubiquitylation (Figure 1B, and see below).
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