Golgi-derived vesicles that contain phosphatidylinositol 3,4-bisphosphate facilitate mitochondrial fusion at sites marked with mitofusins and endoplasmic reticulum.
DNA–protein crosslinks (DPCs) are one of the most complex and deleterious forms of DNA damage. DPCs arise from the stabilization of covalent enzyme–DNA intermediates, such as topoisomerase cleavage complexes, or from exposure to bifunctional crosslinking agents, and they differ in protein identity, DNA context and chemical linkage. Because of their bulky nature, DPCs obstruct essential chromatin processes such as DNA replication and transcription, making their timely removal by dedicated DPC repair pathways crucial for genome stability and cellular homeostasis. In this Review, we discuss the origin and properties of the major classes of DPCs. We also describe key enzymes involved in DPC repair, with a particular focus on the proteasome and the specialized DPC protease SPRTN. Next, we synthesize recent advances in the understanding of proteolytic DPC repair across replication-coupled, transcription-coupled and global genome repair pathways and explain how these pathways converge on ubiquitylation of the crosslinked protein to license proteolysis by the proteasome or SPRTN. Finally, we discuss how defective DPC proteolysis contributes to genome instability, premature ageing and cancer predisposition. DNA–protein crosslinks (DPCs) obstruct essential chromatin processes, and their removal is crucial for genome stability. This Review discusses the origin and properties of DPCs, mechanisms of proteolytic DPC repair, and how defective DPC proteolysis contributes to genome instability, premature ageing and disease.
Similar small RNAs in Caenorhabditis elegans pair with different Argonaute proteins, resulting in differential targeting of nucleic acids and biological outcomes.
The RNA modification N6-methyladenosine (m6A) precisely regulates eukaryotic gene expression. The deposition of m6A is governed by chromatin environment, transcription and RNA processing. m6A modifications influence chromatin function and RNA splicing, stability, localization and translation, and enable cellular adaptation to environmental changes. Dysregulation of m6A has been implicated in pathological processes, including neurodegenerative diseases and cancer. In this Review, we dissect the m6A machinery by describing how writers and erasers coordinate m6A deposition and reader proteins translate these modifications into diverse functional outcomes. We illustrate how this dynamic regulatory network orchestrates cellular stress responses, metabolic homeostasis and antitumour immunity, and outline the pathological consequences of m6A dysregulation in brain disorders and cancer. Finally, we highlight translational prospects of m6A biology, including the development of specific small-molecule inhibitors and precise editing technologies, and address the remaining challenges for clinical interventions targeting m6A. This Review discusses how the RNA modification N6-methyladenosine (m6A) precisely regulates eukaryotic gene expression and orchestrates cellular stress responses, metabolic homeostasis and immunity. It also explores the pathological consequences of m6A dysregulation in brain disorders and cancer.
Although a single type of lipid is sufficient to form a membrane, living cells use hundreds. A genomically minimal cell sustained by just two types of lipids has established a baseline for discovering how lipid diversity enables independent control of membrane properties and how functional membrane phenotypes can be engineered. A synthetic minimal cell can survive with just two lipids, revealing that extensive lipid diversity is not essential for life. This Comment discusses our current understanding of why cells contain so many lipids and highlights future research avenues.
