Regulation of SNAIL1 and E-cadherin function by DNMT1 in a DNA methylation-independent context

Mammalian DNA methyltransferase 1 (DNMT1) is essential for maintaining DNA methylation patterns after cell division. Disruption of DNMT1 catalytic activity results in whole genome cytosine demethylation of CpG dinucleotides, promoting severe dysfunctions in somatic cells and during embryonic development. While these observations indicate that DNMT1-dependent DNA methylation is required for proper cell function, the possibility that DNMT1 has a role independent of its catalytic activity is a matter of controversy. Here, we provide evidence that DNMT1 can support cell functions that do not require the C-terminal catalytic domain. We report that PCNA and DMAP1 domains in the N-terminal region of DNMT1 are sufficient to modulate E-cadherin expression in the absence of noticeable changes in DNA methylation patterns in the gene promoters involved. Changes in E-cadherin expression are directly associated with regulation of β-catenin-dependent transcription. Present evidence suggests that the DNMT1 acts on E-cadherin expression through its direct interaction with the E-cadherin transcriptional repressor SNAIL1 ; MEC (SAF2008-00609 to J.E.); MEC (SAF2007-63051 and Consolider CSD2007-00017); EU (MRTN-CT-2004- 005428 to A.C.); MEC (SAF2004-07729, Consolider CSD2006-49); EU (FP7-CANCERDIP-2007-200620 to M.E.); MEC (SAF2010-19152 to J.R.). M.E. is an ICREA Research Professor. J.E. is a Ramon y Cajal Program researcher (MICIIN). Funding for open access charge: Consolider CSD2006-49 (Grant of the Spanish Science Governmental Department)