Article | Published:

A new MCM modification cycle regulates DNA replication initiation

Nature Structural & Molecular Biology volume 23, pages 209216 (2016) | Download Citation

Abstract

The MCM DNA helicase is a central regulatory target during genome replication. MCM is kept inactive during G1, and it initiates replication after being activated in S phase. During this transition, the only known chemical change to MCM is the gain of multisite phosphorylation that promotes cofactor recruitment. Because replication initiation is intimately linked to multiple biological cues, additional changes to MCM can provide further regulatory points. Here, we describe a yeast MCM SUMOylation cycle that regulates replication. MCM subunits undergo SUMOylation upon loading at origins in G1 before MCM phosphorylation. MCM SUMOylation levels then decline as MCM phosphorylation levels rise, thus suggesting an inhibitory role of MCM SUMOylation during replication. Indeed, increasing MCM SUMOylation impairs replication initiation, partly through promoting the recruitment of a phosphatase that decreases MCM phosphorylation and activation. We propose that MCM SUMOylation counterbalances kinase-based regulation, thus ensuring accurate control of replication initiation.

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Acknowledgements

We are very grateful to T. Zhang and J. Xiang at the Genomics Resources Core Facility, Weill Cornell Medical College for their kind assistance in genome-wide sequencing analyses. We also thank K. Labib (University of Dundee), D. Shore (Institute of Genetics and Genomics in Geneva), B. Stillman (Cold Spring Harbor Laboratory), J. Diffley (Cancer Research UK London Research Institute), D. Remus (Memorial Sloan Kettering Cancer Center), J. Torres-Rosell (Universitat de Lleida), M. Kanemaki (Japan National Institute of Genetics) and D. Koshland (University of California, Berkeley) for providing strains, plasmids and antibodies. We also thank Zhao-laboratory members B. Wan for providing reagents and P. Sarangi for discussion. This study was supported by US National Institutes of Health grant GM080670 to X.Z.

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Affiliations

  1. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Lei Wei
    •  & Xiaolan Zhao
  2. Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Lei Wei

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Contributions

L.W. and X.Z. conceived the study and designed the experiments. L.W. performed the experiments. L.W. and X.Z. analyzed the results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xiaolan Zhao.

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DOI

https://doi.org/10.1038/nsmb.3173