Coster, G.
Diffley, J.F.
(2017). Bidirectional eukaryotic DNA replication is established by quasi-symmetrical helicase loading. Science,
Vol.357
(6348),
pp. 314-318.
Coster, G.
Frigola, J.
Beuron, F.
Morris, E.P.
Diffley, J.F.
(2014). Origin Licensing Requires ATP Binding and Hydrolysis by the MCM Replicative Helicase. Molecular cell,
Vol.55
(5),
pp. 666-677.
Coster, G.
Gold, A.
Chen, D.
Schatz, D.G.
Goldberg, M.
(2012). A Dual Interaction between the DNA Damage Response Protein MDC1 and the RAG1 Subunit of the V(D)J Recombinase. Journal of biological chemistry,
Vol.287
(43),
pp. 36488-36498.
Coster, G.
Goldberg, M.
(2010). The cellular response to DNA damage: A focus on MDC1 and its interacting proteins. Nucleus,
Vol.1
(2),
pp. 166-178.
Coster, G.
Goldberg, M.
(2010). The cellular response to DNA damage: A focus on MDC1 and its interacting proteins. Nucleus,
Vol.1
(2),
pp. 166-178.
Coster, G.
Hayouka, Z.
Argaman, L.
Strauss, C.
Friedler, A.
Brandeis, M.
Goldberg, M.
(2007). The DNA Damage Response Mediator MDC1 Directly Interacts with the Anaphase-promoting Complex/Cyclosome. Journal of biological chemistry,
Vol.282
(44),
pp. 32053-32064.
Rausch, C.
Zhang, P.
Casas-Delucchi, C.S.
Daiß, J.L.
Engel, C.
Coster, G.
Hastert, F.D.
Weber, P.
Cardoso, M.C.
Cytosine base modifications regulate DNA duplex stability and metabolism. Nucleic acids research,
.
show abstract
Abstract
DNA base modifications diversify the genome and are essential players in development. Yet, their influence on DNA physical properties and the ensuing effects on genome metabolism are poorly understood. Here, we focus on the interplay of cytosine modifications and DNA processes. We show by a combination of in vitro reactions with well-defined protein compositions and conditions, and in vivo experiments within the complex networks of the cell that cytosine methylation stabilizes the DNA helix, increasing its melting temperature and reducing DNA helicase and RNA/DNA polymerase speed. Oxidation of methylated cytosine, however, reverts the duplex stabilizing and genome metabolic effects to the level of unmodified cytosine. We detect this effect with DNA replication and transcription proteins originating from different species, ranging from prokaryotic and viral to the eukaryotic yeast and mammalian proteins. Accordingly, lack of cytosine methylation increases replication fork speed by enhancing DNA helicase unwinding speed in cells. We further validate that this cannot simply be explained by altered global DNA decondensation, changes in histone marks or chromatin structure and accessibility. We propose that the variegated deposition of cytosine modifications along the genome regulates DNA helix stability, thereby providing an elementary mechanism for local fine-tuning of DNA metabolism..