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Regulation of the Initiation of DNA Replication upon DNA Damage in Eukaryotes

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The Initiation of DNA Replication in Eukaryotes

Abstract

Cycling cells must ensure homeostasis of the genetic information during repeated chromosome replication-segregation cycles. To guarantee genome stability in normal and DNA damage conditions the initiation of DNA replication in eukaryotes is regulated by the cell cycle machinery and the intra S-phase checkpoint (ISC). The cell cycle kinases CDK and DDK induce initiation specifically in S phase, and the ISC inhibits both kinase pathways, suppressing initiation upon DNA damage and replisome stalling to prevent the replication machinery from having to copy damaged DNA templates. Despite this ISC-mediated inhibition, dormant origins are allowed to fire in genomic regions that are actively engaged in replication when the DNA damage occurs. Forks from dormant origins can rescue replisomes that have stalled at DNA lesions, helping to ensure that no part of these replicating regions is left unreplicated in DNA damage conditions. This replisome rescue also helps prevent stalled and collapsed forks from causing genome rearrangements. In higher eukaryotes, these principles of regulating initiation upon DNA damage must be implemented into a particularly complex temporal regulation programme of genome replication. Molecular details of how the ISC, which poses an important barrier against tumour formation, achieves the regulation of initiation upon DNA damage is only beginning to emerge.

*Both are contributed equally

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Acknowledgements

We are grateful to Belen Gomez Gonzales, Juliane Pfrötzschner, Jenny Bormann, Melisa Merdanovic, Gerben Vader and the members of the Pfander lab for helpful discussions and critical reading of the manuscript. The lab of D. Boos is supported by an NRW Rückkehrerförderprogramm fellowship from the Ministry for Innovation, Science and Research of North Rhine-Westphalia, Germany. The Pfander lab is supported by the Max-Planck Society and the German Research Council (DFG). The authors declare that they have no competing financial interest.

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    1. Molecular Genetics II, Vertebrate DNA Replication, Centre for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, 45117, Germany

      Kerstin Köhler, Pedro Ferreira & Dominik Boos

    2. DNA Replication and Genome Integrity, Max-Planck Institute of Biochemistry, Martinsried, 82152, Germany

      Boris Pfander

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    1. Kerstin Köhler
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    1. Florida State Univ. College of Medi, TALLAHASSEE, Florida, USA

      Daniel L. Kaplan

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    Köhler, K., Ferreira, P., Pfander, B., Boos, D. (2016). Regulation of the Initiation of DNA Replication upon DNA Damage in Eukaryotes. In: Kaplan, D. (eds) The Initiation of DNA Replication in Eukaryotes. Springer, Cham. https://doi.org/10.1007/978-3-319-24696-3_22

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