Abstract
The complete and accurate replication of the genome is a crucial aspect of cell proliferation that is often perturbed during oncogenesis. Replication stress arising from a variety of obstacles to replication fork progression and processivity is an important contributor to genome destabilization. Accordingly, cells mount a complex response to this stress that allows the stabilization and restart of stalled replication forks and enables the full duplication of the genetic material. This response articulates itself on three important platforms, Replication Protein A/RPA-coated single-stranded DNA, the DNA polymerase processivity clamp PCNA and the FANCD2/I Fanconi Anemia complex. On these platforms, the recruitment, activation and release of a variety of genome maintenance factors is regulated by post-translational modifications including mono- and poly-ubiquitylation. Here, we review recent insights into the control of replication fork stability and restart by the ubiquitin system during replication stress with a particular focus on human cells. We highlight the roles of E3 ubiquitin ligases, ubiquitin readers and deubiquitylases that provide the required flexibility at stalled forks to select the optimal restart pathways and rescue genome stability during stressful conditions.
Highlights
Precise and thorough replication of the genome is a pre-requisite for cell proliferation and the faithful transmission of genetic information to the progeny of all living organisms
ATRIP exhibits affinity for K63-linked ubiquitin chains that may favor ATR-ATRIP recruitment onto ubiquitylated RPA-ssDNA. This led to the proposal of a feed-forward loop for ATR activation in which RPA hyper-phosphorylation by ATR, ATM and DNA-PK enhances its interaction with PRP19 and its ubiquitylation by both RFWD3 and PRP19 which may further promote fork restart and homologous recombination (HR) (Figure 2, [21,59])
To the RPA-ssDNA platform, studies revealed that ubiquitylation and/or SUMOylation of PCNA are important for cell survival in response to DNA damaging agents that block replication fork progression such as UV, methyl methanesulfonate, mitomycin C or HU [100,101]
Summary
Precise and thorough replication of the genome is a pre-requisite for cell proliferation and the faithful transmission of genetic information to the progeny of all living organisms. In addition to ATR activation, the ability of RPA to interact with numerous other DNA replication, recombination and repair factors implicates it in virtually all sub-pathways of replication fork processing and restart during replication stress Another key platform for the early RSR is the homotrimeric DNA polymerase sliding clamp PCNA (Proliferating Cell Nuclear Antigen) [39,40]. To RPA, PCNA exerts its cellular functions by interacting with myriad genome maintenance factors that often bind PCNA through a short conserved PIP (PCNA interacting-peptide; consensus sequence Q-x-x-[I/L/M/V]-x-x-[F/Y]-[F/Y]) making this platform an essential component of DNA replication and the RSR [44] Because of their symmetrical architecture, PCNA and its bacterial equivalent the beta sliding clamp can in principle interact productively with multiple different partners simultaneously giving rise to the tool belt hypothesis [45]. We review recent findings on the ubiquitin ligases, ubiquitin-binding genome guardians and de-ubiquitylases that play key roles on the main RSR platforms to faithfully complete DNA replication under adverse conditions
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