Replication of the genetic material DNA is essential for cell proliferation. During this process, not only DNA but also DNA methylation, which is essential epigenetic mark, is maintained from parent to daughter cells. It has been known that DNA methyltransferase 1 (DNMT1) and its activator, UHRF1, are important to maintain DNA methylation. Although it has been recognized primarily as an activator of DNMT1, UHRF1 is also implicated in cancer development, unlike DNMT1, suggesting that it may have functions through other pathways, independent of DNMT1.
To delineate the individual functions of UHRF1 and DNMT1, we utilized the auxin-inducible degron (AID)(In Japanese only) and AID2 system that can induce the total and synchronous depletion of endogenous UHRF1 or DNMT1 proteins in human cancer cells. Interestingly, UHRF1 depletion resulted in a more severe DNA methylation loss than DNMT1 removal. With the combination of whole genome DNA methylation analysis and genetic knock-out techniques, we revealed that UHRF1 regulated not only DNMT1 but also DNA methyltransferases DNMT3A/DNMT3B and demethylase TET2.
Assistant Prof. Kosuke Yamaguchi (formally a postdoctoral researcher at Paris-Cite University) led the study as the first and co-corresponding author in the Pierre-Antoine Defossez laboratory, and Prof. Masato Kanemaki was also involved in this study.
Figure: A revised and expanded model for UHRF1 functions in DNA methylation homeostasis.
