Functions of Ubiquitin and SUMO in DNA Replication and Replication Stress

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.

SUMO conjugation – a mechanistic view

“…SUMO belongs to the superfamily of ubiquitin-like (Ubl) modifiers and performs essential functions in most organisms. Sumoylation is involved in a large variety of fundamental cellular processes, including DNA replication, transcription, cell cycle regulation, DNA damage repair, chromatin organization, ribosome biogenesis, pre-mRNA splicing, nuclear trafficking, signal transduction and protein degradation (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Such a plethora of functions implies the existence of multiple targets.…”

“…Such stress stimuli include DNA damage, heat shock, proteasomal inhibition, viral infection or ischemic challenge. These significant rearrangements in the SUMO proteome appear to represent a versatile immediate stress response, required, for example, for DNA damage repair (2,7,18) or to protect the brain against focal cerebral ischemic damage (19). However, constitutively increased sumoylation has rather negative effects and correlates with resistance to cancer treatments, increased tumor metastasis and relapse (20)(21)(22)(23)(24).…”

Regulation of Mammalian DNA Replication via the Ubiquitin-Proteasome System

“…Together, these factors facilitate nucleosomal disassembly ahead of incoming replication forks and promote their reassembly following their passage. Many of these proteins and protein complexes are regulated through the UPS, and several excellent recent reviews describe these activities in details (Garcia-Rodriguez et al 2016; Talbert and Henikoff 2017; Henikoff 2016; Almouzni and Cedar 2016). In this section, we focus on the role of the UPS in regulating replication initiation, progression, and termination.…”

“…DUBs play a pivotal role as regulators of the turnover rate, activation, recycling, and localization of many proteins and thus are essential for regulating several signaling pathways and for cellular homeostasis (Komander et al 2009; Reyes-Turcu et al 2009). The role of the UPS in controlling DNA replication following replication stress and in response to DNA damage is described in excellent recent reviews (Garcia-Rodriguez et al 2016; Renaudin et al 2016; Sommers et al 2015). In this chapter, we focus on protein ubiquitylation leading to proteasomal degradation or modification of function of key proteins to control DNA replication, with an emphasis on key E3 ubiquitin ligases and DUBs.…”

The Role of the Transcriptional Response to DNA Replication Stress

“…The role of post-translational modifications in regulating and coordinating the response to DNA replication stress has been widely studied [87,88]. Phosphorylation is a key element of the checkpoint response through ATR and Chk1 kinase activity, but ubiquitination and sumolation are also important [89].…”