DNA methylation is a major epigenetic modification that plays critical roles in mammalian embryonic development, differentiation, transcriptional regulation,X-inactivation, imprinting and genome stability.The diverse patterns of DNA methylation in different cells are cooperatively maintained by DNMT1, DNMT3A and DNMT3B.Accumulative studies have demonstrated that UHRF1 is required for DNA maintenance methylation by targeting DNMT1 to DNA replication forks through both of its ability to bind hemi-methylated DNA and K9-methylated histone H3.As a protein closely related to UHRF1, we and others have previously shown that UHRF2 is not involved in targeting DNMT1 for maintenance DNA methylation.In this talk I will present evidence that UHRF2 negatively regulates DNA methylation by functioning as an E3 ligase targeting DNMT3A for ubiquitin-dependent proteasome degradation.Surprisingly, although UHRF1 is essential for DNA maintenance methylation, it also suppresses de novo methylation by targeting DNMT3A degradation.This negative regulation of de novo DNA methylation by UHRF1/2 is conserved and is likely to balance the cellular activity of de novo and maintenance DNA methylation.However, excessive degradation of DNMT3A as a consequence of UHRF1/2 overexpression is causal to and likely a common mechanism for DNA hypomethylation in cancers.Our results provide new insight into regulation of DNA methylation and a mechanism for DNA hypomethylation in cancer.