PRMT1 promotes the tumor suppressor function of p14ARF and is indicative for pancreatic cancer prognosis
Antje Repenning, Daniela Happel, Caroline Bouchard, Marion Meixner, Yesim Verel‐Yilmaz, Hartmann Raifer, Lena Holembowski, Eberhard Krause, Elisabeth Kremmer, Regina Feederle, Corinna U. Keber, Michael Lohoff, Emily P. Slater, Detlef K. Bartsch, Uta‐Maria Bauer
Abstract
The p14 ARF protein is a well-known regulator of p53-dependent and p53-independent tumor-suppressive activities. In unstressed cells, p14 ARF is predominantly sequestered in the nucleoli, bound to its nucleolar interaction partner NPM. Upon genotoxic stress, p14 ARF undergoes an immediate redistribution to the nucleo-and cytoplasm, where it promotes activation of cell cycle arrest and apoptosis. Here, we identify p14 ARF as a novel interaction partner and substrate of PRMT1 (protein arginine methyltransferase 1). PRMT1 methylates several arginine residues in the C-terminal nuclear/nucleolar localization sequence (NLS/NoLS) of p14 ARF . In the absence of cellular stress, these arginines are crucial for nucleolar localization of p14 ARF . Genotoxic stress causes augmented interaction between PRMT1 and p14 ARF , accompanied by arginine methylation of p14 ARF . PRMT1dependent NLS/NoLS methylation promotes the release of p14 ARF from NPM and nucleolar sequestration, subsequently leading to p53independent apoptosis. This PRMT1-p14 ARF cooperation is cancerrelevant and indicative for PDAC (pancreatic ductal adenocarcinoma) prognosis and chemotherapy response of pancreatic tumor cells. Our data reveal that PRMT1-mediated arginine methylation is an important trigger for p14 ARF 's stress-induced tumor-suppressive function.