Abstract
Post-translational modification of the DNA replication machinery by ubiquitin and SUMO plays key roles in the faithful duplication of the genetic information. Among other functions, ubiquitination and SUMOylation serve as signals for the extraction of factors from chromatin by the AAA ATPase VCP. In addition to the regulation of DNA replication initiation and elongation, we now know that ubiquitination mediates the disassembly of the replisome after DNA replication termination, a process that is essential to preserve genomic stability. Here, we review the recent evidence showing how active DNA replication restricts replisome ubiquitination to prevent the premature disassembly of the DNA replication machinery. Ubiquitination also mediates the removal of the replisome to allow DNA repair. Further, we discuss the interplay between ubiquitin-mediated replisome disassembly and the activation of CDK1 that is required to set up the transition from the S phase to mitosis. We propose the existence of a ubiquitin–CDK1 relay, where the disassembly of terminated replisomes increases CDK1 activity that, in turn, favors the ubiquitination and disassembly of more replisomes. This model has important implications for the mechanism of action of cancer therapies that induce the untimely activation of CDK1, thereby triggering premature replisome disassembly and DNA damage.
Highlights
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In addition to the SUMOylation of specific factors, we have proposed that the collective SUMOylation of the replication machinery supports DNA replication by creating an environment that facilitates interactions among replication factors [84], analogous to the SUMO-based group modification model proposed by Stefan Jentsch for DNA repair [85]
This is relevant in light of the recent advances showing how ubiquitin and SUMO are essential for disassembly of the replication machinery after DNA replication termination, as we develop
Summary
Post-translational modifications (PTMs) play key roles in the cell as essential regulators of the spatiotemporal control of protein function. SUMO2/3 forms chains and can participate in mixed ubiquitin/SUMO chains This “ubiquitin code” establishes a set of specific modifications with different functional outcomes by modifying the stability, localization, activity or interactome of the target proteins. One of the main transducers of ubiquitin and SUMO is the AAA ATPase VCP (valosin containing protein), known as p97 segregase, a central factor in the regulation of protein homeostasis [6,7,8,9] that mobilizes the chromatin-bound substrates conjugated to ubiquitin [10,11,12] or ubiquitin-like molecules [13,14,15,16] To this end, VCP uses a repertoire of adaptors/cofactors which recognize poly-ubiquitinated substrates through their ubiquitinbinding domains [17,18]. Ub and SUMO constitute a complex post-translational modification system that affects many essential cellular functions, including the regulation of DNA metabolism and genome stability [26]
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