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Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation.

Schermelleh, Lothar and Haemmer, Andrea and Spada, Fabio and Rösing, Nicole and Meilinger, Daniela and Rothbauer, Ulrich and Cardoso, M Cristina and Leonhardt, Heinrich (2007):
Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation.
In: Nucleic acids research, pp. 4301-12, 35, (13), ISSN 1362-4962,
[Online-Edition: http://www.cardoso-lab.org/publications/Schermelleh_et_al_20...],
[Article]

Abstract

Postreplicative maintenance of genomic methylation patterns was proposed to depend largely on the binding of DNA methyltransferase 1 (Dnmt1) to PCNA, a core component of the replication machinery. We investigated how the slow and discontinuous DNA methylation could be mechanistically linked with fast and processive DNA replication. Using photobleaching and quantitative live cell imaging we show that Dnmt1 binding to PCNA is highly dynamic. Activity measurements of a PCNA-binding-deficient mutant with an enzyme-trapping assay in living cells showed that this interaction accounts for a 2-fold increase in methylation efficiency. Expression of this mutant in mouse dnmt1-/- embryonic stem (ES) cells restored CpG island methylation. Thus association of Dnmt1 with the replication machinery enhances methylation efficiency, but is not strictly required for maintaining global methylation. The transient nature of this interaction accommodates the different kinetics of DNA replication and methylation while contributing to faithful propagation of epigenetic information.

Item Type: Article
Erschienen: 2007
Creators: Schermelleh, Lothar and Haemmer, Andrea and Spada, Fabio and Rösing, Nicole and Meilinger, Daniela and Rothbauer, Ulrich and Cardoso, M Cristina and Leonhardt, Heinrich
Title: Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation.
Language: English
Abstract:

Postreplicative maintenance of genomic methylation patterns was proposed to depend largely on the binding of DNA methyltransferase 1 (Dnmt1) to PCNA, a core component of the replication machinery. We investigated how the slow and discontinuous DNA methylation could be mechanistically linked with fast and processive DNA replication. Using photobleaching and quantitative live cell imaging we show that Dnmt1 binding to PCNA is highly dynamic. Activity measurements of a PCNA-binding-deficient mutant with an enzyme-trapping assay in living cells showed that this interaction accounts for a 2-fold increase in methylation efficiency. Expression of this mutant in mouse dnmt1-/- embryonic stem (ES) cells restored CpG island methylation. Thus association of Dnmt1 with the replication machinery enhances methylation efficiency, but is not strictly required for maintaining global methylation. The transient nature of this interaction accommodates the different kinetics of DNA replication and methylation while contributing to faithful propagation of epigenetic information.

Journal or Publication Title: Nucleic acids research
Volume: 35
Number: 13
Divisions: 10 Department of Biology > Cell Biology and Epigenetics
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10 Department of Biology
Date Deposited: 06 Mar 2010 15:45
Official URL: http://www.cardoso-lab.org/publications/Schermelleh_et_al_20...
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