Mutation in RAS gene is one of the most common genetic alterations, which seems to be seen in one third of human cancers. Ras, as a molecular switch, has been considered in wide variety of signaling pathways such as cell division and apoptosis. Ras proteins have a binary function to transmit different extracellular messages into intracellular signaling network. It has been proved that Ras proteins associate with different plasma membranes. Although all Ras isoforms have been found at plasma membrane, H-Ras and N-Ras are located in Golgi, and K-Ras at ER and mitochondria outer membrane. There have been a lot of efforts to inhibit Ras signaling that can be a pivotal approach to treat Ras-induced tumors. Effect of RalA and RalB on the growth of embryonal tumors, at downstream region of Ras, has been studied in a number of studies, which showed that inhibition of these signaling pathways can provide a strong therapeutic approach to cancer. Also, post translational modifications (PTMs) in proteins interfere extremely with cell signaling pathways in cells that can react to external signals. In this review, the role of Ral signaling in cancer and PTM of Ras proteins has been reviewed.
Cells are often under attack from various DNA-damaging agents. Accurate repair is required to protect cells from the genome instability induced by DNA lesions. DNA damage response (DDR) signaling involves sensitizing, transmitting, and repairing different types of damage within chromatin complexes. Chromatin is a highly ordered complex packed with repeating units of nucleosomes and linker DNA sequences. Chromatin structure, gene transcription, and various biological processes are regulated by histone post-translational modifications (PTMs), including acetylation, methylation, phosphorylation, and ubiquitylation. Of these, the involvement of lysine methylation, regulated by numerous lysine methyltransferases and demethylases, in the DDR has been extensively explored. In particular, histone 4 lysine 20 methylation is one of the most essential histone PTMs for biological processes and ensures genome integrity. In this review, we summarize the dynamics and modulations of histone lysine methylation during the DDR. We also comprehensively describe the functions, mechanisms, and regulation of H4K20 methylation and its modifying enzymes in response to DNA damage.
Autophagy is a major degradation process that degrades and recycles cytoplasmic materials through lysosome for maintaining cellular homeostasis. Dysregulated autophagy is linked with numerous human diseases including cancer. Autophagy marker protein B-cell lymphoma-2 interacting protein 1 (Beclin-1) is essential for autophagosome initiation and maturation. Recently, Ubiquitin carboxyl-terminal hydrolase 11 (USP11) has been reported to promote or inhibit autophagy without identification of any direct target. Here through biochemical reaction in vitro, we demonstrate that USP11 directly interacts with Beclin-1. Both in vitro and in vivo de-ubiquitination assays revealed that USP11 de-ubiquitinates Beclin-1. USP11-mediated de-ubiquitination stabilized Beclin-1 and enhanced the formation of the autophagy-specific class III phosphatidylinositol 3-kinase complexes 1 and 2, thereby promoting autophagy. Together, our results demonstrated that USP11 promotes autophagy under unperturbed conditions by de-ubiquitinating and stabilizing Beclin-1 which may serve as a therapeutic target for autophagy-related diseases.