Regulation of the DNA‐binding Protein CFP1 by ERK1/2

CFP1 (CXXC finger protein 1) was identified in our lab as an ERK2 interactor through a yeast two‐hybrid screen. CFP1 binds to the maintenance cytosine methyltransferase DNMT1 and is required for DNA methylation in an embryonic model. Methylation of DNA in promoter regions is critical for transcriptional silencing throughout development and is often dysregulated in cancer. ERK2 is required for KRAS‐driven aberrant gene silencing via promoter methylation by DNMT1, but ERK2 substrates that may mediate this effect have not been identified. I propose that CFP1 is the major ERK2 substrate that directs DNA methylation by promoting the targeting or activity of DNMT1. ERK2‐bound mononucleosomes are enriched for CFP1. Active ERK2 can phosphorylate CFP1 on multiple sites in vitro. Current work is focused on determining the requirement for CFP1 in KRAS‐driven gene silencing, and dissecting the relationship between promoter methylation and the presence of active ERK2 at DNA methylation sites guided by ERK2 ChIP‐sequencing data from a lung cancer model. If ERK1/2 targeting of CFP1 helps to drive directed DNMT1 activity and tumor suppressor gene silencing, it would cement a clear mechanistic linkage between a common activating mutation in cancer and conserved downstream epigenetic effects that promote development of the disease.This work was supported by NIGMS Training Grant T32 GM008203 and by NIH R37 DK34128.