In mammals, DNA methylation plays a crucial role in the regulation of gene expression, telomere length, cell differentiation, X chromosome inactivation, genomic imprinting and tumorigenesis1. DNA methylation patterns are established de novo by DNA methyltransferases (DNMTs) 3a and 3b, whereas DNMT1 maintains the parent-specific methylation from parental cells to their progeny2. After DNA replication, the new DNA strand is unmethylated. Thus with the mother methylated strand, the DNA is hemimethylated. The protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) recognizes and binds to the hemimethylated sites by its SRA domain. Then DNMT1 is recruited to the sites by the same domain, thereby it methylates the newly synthesized DNA strand3, 4. Increased DNMT1 abundance has been seen in many human cancers, and the roles of DNMT1 in tumorigenesis have been shown by some genetic knockout and RNA interference-mediated knockdown studies5, 6. Seeing that the mRNA abundance of DNMT1 contributes less to DNMT1 abundance, the stability of DNMT1 protein therefore plays an important role in human cancers7, 8.

They identified deubiquitinase HAUSP (herpesvirus-associated ubiquitin specific protease) as a DNMT1-associated protein. Knockout or knockdown of HAUSP increased DNMT1 ubiquitination and reduced its abundance, then they demonstrated the direct deubiquitination of DNMT1 in vitro by purified HAUSP recombinant proteins. They also found that overexpression of DNMT1-associated E3 ligase UHRF1 led to increased ubiquitination of DNMT1 and decreased abundance of DNMT1 mutant lacking the HAUSP interaction domain, but not the full-length protein. These results show the coordination between ubiquitination of DNMT1 by UHRF1 and deubiquitination by HAUSP. Furthermore, they found that knockdown of HDAC1 increased DNMT1 acetylation, and reduced DNMT1 abundance. Additionally, acetyltransferase Tip60 which was found to acetylate DNMT1 promoted its ubiquitination, then destabilized it. At last, Tip60 and HAUSP were found to regulate DNMT1 protein stability during the cell cycle. The following clinical samples of human colon cancer also revealed the correlation between the abundance of HAUSP and the abundance of DNMT1.

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