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Review
. 2018 Sep 20;7(10):146.
doi: 10.3390/cells7100146.

Control of DNA Replication Initiation by Ubiquitin

Esperanza Hernández-Carralero  1 , Elisa Cabrera  2 , Ignacio Alonso-de Vega  3 , Santiago Hernández-Pérez  4   5 , Veronique A J Smits  6 , Raimundo Freire  7
Affiliations
Review

Control of DNA Replication Initiation by Ubiquitin

Esperanza Hernández-Carralero et al. Cells. .

Abstract

Eukaryotic cells divide by accomplishing a program of events in which the replication of the genome is a fundamental part. To ensure all cells have an accurate copy of the genome, DNA replication occurs only once per cell cycle and is controlled by numerous pathways. A key step in this process is the initiation of DNA replication in which certain regions of DNA are marked as competent to replicate. Moreover, initiation of DNA replication needs to be coordinated with other cell cycle processes. At the molecular level, initiation of DNA replication relies, among other mechanisms, upon post-translational modifications, including the conjugation and hydrolysis of ubiquitin. An example is the precise control of the levels of the DNA replication initiation protein Cdt1 and its inhibitor Geminin by ubiquitin-mediated proteasomal degradation. This control ensures that DNA replication occurs with the right timing during the cell cycle, thereby avoiding re-replication events. Here, we review the events that involve ubiquitin signalling during DNA replication initiation, and how they are linked to human disease.

Keywords: DNA replication Initiation; proteasome; ubiquitin; ubiquitin hydrolases; ubiquitin ligases.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Main events during initiation of DNA replication and control by ubiquitination. Schematic presentation of the events occurring during DNA replication initiation (early events at the top and later at the bottom) with the main regulators in each stage. Proteins involved in this process that are modified by ubiquitin, and if known, the ubiquitin ligase(s) and/or the deubiquitinating enzyme(s) (DUB(s)) controlling this modification, are depicted. See text for details.
Figure 2
Figure 2
Regulation of Cdt1 and Geminin protein levels by ubiquitination-mediated degradation. (A) Domain structure of human Cdt1 and human Geminin. For Cdt1, the regulation motifs of the N-terminal domain (PIP box, Cdt2-recognizing degron motifs, the Skp2 recognition site, and the three destruction boxes), the middle winged helix domain (WHD), the C-terminal WHD, and the region interacting with Geminin are represented. Geminin structure contains a destruction box, a coiled-coil domain, a Cdt1 interacting region, and a nuclear localization signal (NLS). (B) Diagram presenting Cdt1 and Geminin protein levels, and its regulators, during the cell cycle. The y-axis presents the levels of the two proteins and the x-axis the progression through the cell cycle. The ubiquitin ligases and DUBs controlling these proteins, the recruitment of MCM by Cdt1, and the Geminin–Cdt1 interaction are additionally depicted.
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