Current Opinion in Cell Biology最新文献

In actively dividing eukaryotic cells, the nuclear envelope membrane (NEM) expands during the cell cycle to accommodate increases in nuclear volume and formation of two nuclei as a cell passes through mitosis to form daughter cells. NEM expansion is driven by glycerophospholipid (GPL) synthesis that is regulated by the lipin family of phosphatidic acid phosphatases (PAPs). How, and when during the cell cycle, PAPs regulate membrane expansion differs between organisms undergoing a closed or open mitosis. Here, we discuss recent studies that shed light on the mechanisms of NE expansion. Moreover, we examine evidence that NEM expansion not only employs GPLs synthesized in the ER but also lipids whose synthesis is regulated by events at the inner nuclear membrane.

In recent years, the role of 53BP1 as a cell cycle regulator has come into the spotlight. 53BP1 is best understood for its role in controlling DNA double-strand break repair. However, 53BP1 was initially discovered as an interaction partner of the tumor suppressor p53, which proved to be independent of DNA repair. The importance of this interaction is becoming increasingly clear. 53BP1 responds to mitotic stress, which prolongs mitosis, or to DNA damage and triggers the stabilization of p53 by the deubiquitinase USP28 to stop the proliferation of potentially damaged cells. The ability of 53BP1 to respond to mitotic stress or DNA damage is controlled by cell cycle-specific post-translational modifications and is therefore restricted to specific cell cycle phases. 53BP1-mediated p53 activation is likely involved in tumor suppression and is associated with genetic diseases such as primary microcephaly. This review emphasizes the importance of these mechanisms for the development and maintenance of healthy tissues.

Many solid tumors exhibit significant genetic, cellular, and biophysical heterogeneity which dynamically evolves during disease progression and after treatment. This constant flux in cell composition, phenotype, spatial relationships, and tissue properties poses significant challenges in accurately diagnosing and treating patients. Much of the complexity lies in unraveling the molecular changes in different tumor compartments, how they influence one another in space and time and where vulnerabilities exist that might be appropriate to target therapeutically. Recent advances in spatial profiling tools and technologies are enabling new insight into the underlying biology of complex tumors, creating a greater understanding of the intricate relationship between cell types, states, and the microenvironment. Here we reflect on some recent discoveries in this area, where the key knowledge and technology gaps lie, and the advancements in spatial measurements and in vitro models for the study of spatial intratumoral heterogeneity.

Physical parameters such as tissue interplay forces, luminal pressure, fluid flow, temperature, and electric fields are crucial regulators of embryonic morphogenesis. While significant attention has been given to cellular and molecular responses to these physical parameters, their roles in morphogenesis are not yet fully elucidated. This is largely due to a shortage of methods for spatiotemporal modulation and direct quantitative perturbation of physical parameters in embryos. Recent advancements addressing these challenges include microscopes equipped with devices to apply and adjust forces, direct perturbation of luminal pressure, and the application of micro-forces to targeted cells and cilia in vivo. These methods are critical for unveiling morphogenesis mechanisms, highlighting the importance of integrating molecular and physical approaches for a comprehensive understanding of morphogenesis.

S.J. Gould and R. Lewontin in their famous “Spandrels paper” (1979) argued that many anatomical elements arise in evolution not due to their “current utility” but rather due to other “reasons for origin”, such as other developmental processes, physical constraints and mechanical forces. Here, in the same spirit, we argue that a variety of molecular processes, physical constraints, and mechanical forces, alone or together, generate structures that are detectable in the cell nucleus, yet these structures themselves may not carry any specific function, being a mere reflection of processes that produced them.

The dynamic actin cytoskeleton contributes to many critical biological processes by providing the structural support underlying the morphology of most cells, facilitating intracellular transport, and generating forces required for cell motility and division. To execute many of these functions, actin monomers polymerize into polarized filaments that display different structural and biochemical properties at each end. Filament dynamics are regulated by diverse regulatory proteins which collaborate to dictate rates of elongation and disassembly, particularly at the fast-growing barbed (plus) end. This review highlights the biochemical mechanisms of six barbed end regulatory proteins: formin, profilin, capping protein, IQGAP1, cyclase-associated protein, and twinfilin. We discuss how individual proteins influence actin dynamics and how several intriguing complex assemblies influence the polymerization fate of actin filaments. Understanding these mechanisms offers insights into how actin is regulated in essential cell processes and dysregulated in disease.

Since the advent of Hi-C in 2009, a plethora of high-throughput sequencing methods have emerged to profile the three-dimensional (3D) organization of eukaryotic genomes, igniting the era of 3D genomics. In recent years, the genomic resolution achievable by these approaches has dramatically increased and several single-cell versions of Hi-C have been developed. Moreover, a new repertoire of tools not based on proximity ligation of digested chromatin has emerged, enabling the investigation of the higher-order organization of chromatin in the nucleus. In this review, we summarize the expanding portfolio of 3D genomic technologies, highlighting recent developments and applications from the past three years. Lastly, we present an outlook of where this technology-driven field might be headed.

Cell biology emerges from spatiotemporally coordinated molecular processes. Recent advances in live-cell microscopy, fueled by a surge in optical, molecular, and computational technologies, have enabled dynamic observations from single molecules to whole organisms. Despite technological leaps, there is still an untapped opportunity to fully leverage their capabilities toward biological insight. We highlight how single-molecule imaging has transformed our understanding of biological processes, with a focus on chromatin organization and transcription in the nucleus. We describe how this was enabled by the close integration of new imaging techniques with analysis tools and discuss the challenges to make a comparable impact at larger scales from organelles to organisms. By highlighting recent successful examples, we describe an outlook of ever-increasing data and the need for seamless integration between dataset visualization and quantification to realize the full potential warranted by advances in new imaging technologies.

The spatial separation of protein synthesis from the compartmental destiny of proteins led to the evolution of transport systems that are efficient and yet highly specific. Co-translational transport has emerged as a strategy to avoid cytosolic aggregation of folding intermediates and the need for energy-consuming unfolding strategies to enable transport through narrow conduits connecting compartments. While translation and compartmental translocation are at times tightly coordinated, we know very little about the temporal coordination of translation, protein folding, and nuclear import. Here, we consider the implications of co-translational engagement of nuclear import machinery. We propose that the dynamic interplay of karyopherins and intrinsically disordered nucleoporins create a favorable protein folding environment for cargo en route to the nuclear compartment while maintaining a barrier function of the nuclear pore complex. Our model is discussed in the context of neurological disorders that are tied to defects in nuclear transport and protein quality control.