In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies.

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.

Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and associated with poor prognosis and survival. However, the regulatory mechanisms of PRMT5 remain poorly understood. Here, we report that TRAF6 serves as an upstream E3 ubiquitin ligase to promote PRMT5 ubiquitination and activation. We find that TRAF6 catalyzes K63-linked ubiquitination of PRMT5 and interacts with PRMT5 in a TRAF6-binding-motif-dependent manner. Moreover, we identify six lysine residues located at the N-terminus as the primarily ubiquitinated sites. Disruption of TRAF6-mediated ubiquitination decreases PRMT5 methyltransferase activity towards H4R3 in part by impairing PRMT5 interaction with its co-factor MEP50. As a result, mutating the TRAF6-binding motifs or the six lysine residues significantly suppresses cell proliferation and tumor growth. Lastly, we show that TRAF6 inhibitor enhances cellular sensitivity to PRMT5 inhibitor. Therefore, our study reveals a critical regulatory mechanism of PRMT5 in cancers.

Fli-1, a member of the ETS transcription factor family, has been implicated in multiple inflammatory and immune-related disorders, including sepsis, lupus, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Recent studies further suggest a critical role for Fli-1 in CD4⁺ T cells in graft-versus-host disease, systemic sclerosis, and PTSD; however, its precise function and regulation during inflammatory CD4⁺ T cell responses remain incompletely understood. Wild-type and CD4⁺ T cell-specific Fli-1 knockout mice were administered LPS via intraperitoneal injection. Survival rates and splenic T cell activation were subsequently assessed. In vitro, cultured Jurkat and HEK cells were utilized to investigate the STUB1/Fli-1-related signaling pathway. Here, we demonstrate that Fli-1 expression is markedly upregulated in splenic CD4⁺ T cells in a murine model of endotoxemia. CD4⁺ T cell-specific deletion of Fli-1 significantly improves survival and attenuates splenic CD4⁺ T cell activation. Mechanistically, we identify STUB1 as a novel E3 ubiquitin ligase for Fli-1 that promotes K27-linked ubiquitination and proteasomal degradation under basal conditions. Inflammatory stimulation disrupts the STUB1/HSP70 interaction, reducing STUB1-mediated ubiquitination and enhancing Fli-1 protein stability. Consistent with these findings, Fli-1 knockout reduces TNFα, IFNγ, and IL-10 expression, whereas STUB1 knockout enhances their expression in Jurkat cells. Gain- and loss-of-function studies further reveal that Fli-1 modulates NFκB signaling, a key pathway in T cell activation. Collectively, our results identify the STUB1/Fli-1 axis as a previously unrecognized regulator of CD4⁺ T cell function and a potential therapeutic target for inflammatory diseases.