Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding

Abstract

Flap endonuclease 1 (FEN1), a structure-specific endo- and exo- nuclease, exhibits multiple functions that determine essential biological processes, such as cell proliferation and cell death. As such, the enzyme must be precisely regulated in order to execute each of its functions with the right timing and in a specific subcellular location. Here, we report that FEN1 is methylated at arginine residues, primarily at R192. The methylation suppresses FEN1 phosphorylation at S187. The methylated form, but not the phosphorylated form of FEN1, strongly interacts with Proliferating Cell Nuclear Antigen (PCNA), ensuring the on and off timing of its reaction. Mutations of FEN1 disrupting arginine methylation and PCNA interaction result in unscheduled phosphorylation and cause failure of its localization to DNA replication or repair foci. This consequently leads to a defect in Okazaki fragment maturation, a delay of cell cycle progression, impairment of DNA repair, and high frequency of genome-wide mutations.