Abstract
The maintenance of DNA methylation in nascent DNA is a critical event for numerous biological processes. Following DNA replication, DNMT1 is the key enzyme that strictly copies the methylation pattern from the parental strand to the nascent DNA. However, the mechanism underlying this highly specific event is not thoroughly understood. In this study, we identified topoisomerase IIα (TopoIIα) as a novel regulator of the maintenance DNA methylation. UHRF1, a protein important for global DNA methylation, interacts with TopoIIα and regulates its localization to hemimethylated DNA. TopoIIα decatenates the hemimethylated DNA following replication, which might facilitate the methylation of the nascent strand by DNMT1. Inhibiting this activity impairs DNA methylation at multiple genomic loci. We have uncovered a novel mechanism during the maintenance of DNA methylation.
Highlights
UHRF1 is required for the maintenance of DNA methylation
We found that TopoII␣ was significantly enriched at pericentric heterochromatin (PCH) and co-localized with UHRF1 and 5-methylcytosine (Fig. 2c), suggesting that TopoII␣ is functionally linked with UHRF1 in the maintenance of DNA methylation
In Uhrf1 knock-out embryonic stem (ES) cells, DNMT1 localization at PCH was abolished, which clearly demonstrates that UHRF1 regulates DNA methylation through targeting DNMT1 to hemimethylated DNA
Summary
UHRF1 is required for the maintenance of DNA methylation. Results: UHRF1 interacts with topoisomerase II and regulates its localization to pericentric heterochromatin. TopoII␣ decatenates the hemimethylated DNA following replication, which might facilitate the methylation of the nascent strand by DNMT1. Inhibiting this activity impairs DNA methylation at multiple genomic loci. Loss of DNMT1 in mice induces significant reduction of DNA methylation and leads to embryonic lethality [1] It is not fully clear how DNMT1 recognizes and methylates hemimethylated DNA following replication. Besides DNMT1, recent studies have shown that UHRF1 is required for the maintenance of DNA methylation following DNA replication. Inhibiting topoisomerase activities partially affects DNA methylation in vivo, suggesting that UHRF1 might regulates the maintenance of DNA methylation through TopoII␣
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