The LIM protein AJUBA recruits protein arginine methyltransferase 5 (PRMT5) to mediate SNAIL-dependent transcriptional repression

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104; Department of Medicine, Washington University, St. Louis, MO 63110, USA; Department of Biological Sciences, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431

^* To whom correspondence should be addressed. Email: Rauscher{at}wistar.org.

	Abstract

The SNAIL transcription factor contains C-terminal tandem zinc finger motifs and an N-terminal SNAG repression domain. The SNAIL family has recently emerged as major contributors to the processes of development and metastasis via regulating epithelial-mesenchymal transition events during embryonic development and tumor progression. However, the mechanisms by which SNAIL represses gene expression are largely undefined. Previously we demonstrated that the AJUBA family of LIM proteins, function as co-repressors for SNAIL and, as such, may serve as a platform for assembly of chromatin modifying factors. Here, we describe the identification of the protein arginine methyltransferase 5 (PRMT5) as an effector recruited to SNAIL through an interaction with AJUBA and functions to repress the SNAIL target gene, E-cadherin. PRMT5 binds to the non-LIM region of AJUBA, and is translocated into the nucleus in a SNAIL and AJUBA-dependent manner. Depletion of PRMT5 in p19 cells stimulates E-cadherin expression, and the SNAIL, AJUBA and PRMT5 ternary complex can be found at the the proximal promoter region of the E-cadherin gene, concomitant with increased arginine methylation of histones at the locus. Together, these data suggest that PRMT5 is an effector of SNAIL-dependent gene repression.