Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Aug 16;22(16):8796.
doi: 10.3390/ijms22168796.

Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1

Antonio Galarreta  1 , Pablo Valledor  1 , Oscar Fernandez-Capetillo  1   2 , Emilio Lecona  3
Affiliations
Review

Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1

Antonio Galarreta et al. Int J Mol Sci. .

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.

Keywords: CDK1; DNA replication; SUMO; USP7; mitosis; ubiquitin.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Control of DNA replication initiation by the ubiquitin and SUMO pathways. Model for the assembly of the pre-RC complex and the different layers of control by ubiquitination and SUMOylation of the initiation machinery. CMG is the replicative helicase composed of CDC45, the MCM2-7 complex and the GINS complex.
Figure 2
Figure 2
Models for replisome disassembly. (A) Disassembly of terminated replisomes during the S phase (left) and in mitosis (right) is mediated by the ubiquitination of MCM7 with specific E3 ubiquitin ligases. (B) Replisome disassembly under replication stress is mediated by the CDK1-dependent activation of TRAIP to ubiquitinate MCM7. (C) Replisome disassembly in the presence of SSBs. When the SSB is in the leading strand (left), the CMG slides off the break, while a SSB in the lagging strand leads to CMG translocation along dsDNA and its ubiquitination by CRL2LRR1 (right). (D) In the presence of ICLs, replication forks convergence and MCM7 is ubiquitinated at K48 by TRAIP. Long ubiquitin chains lead to CMG unloading (left) and repair through the FA pathway, whereas short ubiquitin chains activate the NEIL3 glycosylase pathway (right).
Figure 3
Figure 3
Ubiquitination links DNA replication and CDK1. (A) Model for the ubiquitin/CDK1 relay in DNA replication. Active DNA replication forks and USP7 suppress CMG ubiquitination and CDK1 activation to prevent premature entry in mitosis. Accumulating CDK1 activity promotes CMG ubiquitination, leading to disassembly of the terminated replisomes before cell division, or disassembly of the stalled forks inducing DNA damage. (B) Therapeutic implications for the ubiquitin–CDK1 connection. Targeting the ubiquitin pathway might be an alternative way to prematurely activate CDK1 and lead to cell death.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Damgaard R.B. The ubiquitin system: From cell signalling to disease biology and new therapeutic opportunities. Cell Death Differ. 2021;28:423–426. doi: 10.1038/s41418-020-00703-w. - DOI - PMC - PubMed
    1. Meluh P.B., Koshland D. Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol. Biol. Cell. 1995;6:793–807. doi: 10.1091/mbc.6.7.793. - DOI - PMC - PubMed
    1. Seufert W., Futcher B., Jentsch S. Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins. Nature. 1995;373:78–81. doi: 10.1038/373078a0. - DOI - PubMed
    1. Tatham M.H., Jaffray E., Vaughan O.A., Desterro J.M.P., Botting C.H., Naismith J.H., Hay R.T. Polymeric Chains of SUMO-2 and SUMO-3 are Conjugated to Protein Substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 2001;276:35368–35374. doi: 10.1074/jbc.M104214200. - DOI - PubMed
    1. Komander D., Rape M. The Ubiquitin Code. Annu. Rev. Biochem. 2012;81:203–229. doi: 10.1146/annurev-biochem-060310-170328. - DOI - PubMed

Substances

LinkOut - more resources