Tap73 is essential for germ cell adhesion and maturation in testis

A core evolutionary function of the p53 family is to protect the genomic integrity of gametes. However, the role of p73 in the male germ line is unknown. Here, we reveal that TAp73 unexpectedly functions as an adhesion and maturation factor of the seminiferous epithelium orchestrating spermiogenesis. TAp73 knockout (TAp73KO) and p73KO mice, but not ΔNp73KO mice, display a “near-empty seminiferous tubule” phenotype due to massive premature loss of immature germ cells. The cellular basis of this phenotype is defective cell–cell adhesions of developing germ cells to Sertoli nurse cells, with likely secondary degeneration of Sertoli cells, including the blood–testis barrier, which leads to disruption of the adhesive integrity and maturation of the germ epithelium. At the molecular level, TAp73, which is produced in germ cells, controls a coordinated transcriptional program of adhesion- and migration-related proteins including peptidase inhibitors, proteases, receptors, and integrins required for germ–Sertoli cell adhesion and dynamic junctional restructuring. Thus, we propose the testis as a unique organ with strict division of labor among all family members: p63 and p53 safeguard germ line fidelity, whereas TAp73 ensures fertility by enabling sperm maturation

PRMT1 promotes the tumor suppressor function of p14^ARF and is indicative for pancreatic cancer prognosis.

The p14 protein is a well-known regulator of p53-dependent and p53-independent tumor-suppressive activities. In unstressed cells, p14 is predominantly sequestered in the nucleoli, bound to its nucleolar interaction partner NPM. Upon genotoxic stress, p14 undergoes an immediate redistribution to the nucleo- and cytoplasm, where it promotes activation of cell cycle arrest and apoptosis. Here, we identify p14 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 . In the absence of cellular stress, these arginines are crucial for nucleolar localization of p14 . Genotoxic stress causes augmented interaction between PRMT1 and p14 , accompanied by arginine methylation of p14 . PRMT1-dependent NLS/NoLS methylation promotes the release of p14 from NPM and nucleolar sequestration, subsequently leading to p53-independent apoptosis. This PRMT1-p14 cooperation is cancer-relevant 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 ’s stress-induced tumor-suppressive function. ARF ARF ARF ARF ARF ARF ARF ARF ARF ARF AR