Cytosine base modifications regulate DNA duplex stability and metabolism.
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ICR Authors
Authors
Rausch, C
Zhang, P
Casas-Delucchi, CS
Daiß, JL
Engel, C
Coster, G
Hastert, FD
Weber, P
Cardoso, MC
Zhang, P
Casas-Delucchi, CS
Daiß, JL
Engel, C
Coster, G
Hastert, FD
Weber, P
Cardoso, MC
Document Type
Journal Article
Date
2021-12-16
Date Accepted
2021-06-03
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.
Citation
Nucleic acids research, 2021
Source Title
Publisher
OXFORD UNIV PRESS
ISSN
0305-1048
eISSN
1362-4962
Collections
Research Team
Genome Replication
Genome Replication
Genome Replication