Nature Reviews Molecular Cell Biology最新文献

Programmed cell death is a mechanism that is crucial for numerous physiological and pathological processes. Whereas p53-mediated apoptosis is a major cell death pathway in cancer, accumulating evidence indicates that p53 also has crucial roles in controlling different non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis, pyroptosis, autophagy-dependent cell death, entotic cell death, parthanatos and paraptosis, and may regulate PANoptosis, cuproptosis and disulfidptosis. Notably, the function of p53 in these NACDs substantially contributes to its biological effects, particularly in cancer development and other pathological processes. In this Review, we discuss recent advances in understanding the roles and underlying mechanisms of p53-mediated NACDs, focusing on ferroptosis, necroptosis and pyroptosis. We discuss the complex and distinct physiological settings in which NACDs are regulated by p53, and potential targeting of p53-regulated NACDs for the treatment of cancer and other human diseases. Finally, we highlight several important questions concerning p53-regulated NACDs that warrant further investigation.

Ferroptosis is a necrotic, non-apoptotic cell death modality triggered by unrestrained iron-dependent lipid peroxidation. By unveiling the regulatory mechanisms of ferroptosis and its relevance to various diseases, research over the past decade has positioned ferroptosis as a promising therapeutic target. The rapid growth of this research field presents challenges, associated with potentially inadequate experimental approaches that may lead to misinterpretations in the assessment of ferroptosis. Typical examples include assessing whether an observed phenotype is indeed linked to ferroptosis, and selecting appropriate animal models and small-molecule modulators of ferroptotic cell death. This Expert Recommendation outlines state-of-the-art methods and tools to reliably study ferroptosis and increase the reproducibility and robustness of experimental results. We present highly validated compounds and animal models, and discuss their advantages and limitations. Furthermore, we provide an overview of the regulatory mechanisms and the best-studied players in ferroptosis regulation, such as GPX4, FSP1, SLC7A11 and ACSL4, discussing frequent pitfalls in experimental design and relevant guidance. These recommendations are intended for researchers at all levels, including those entering the expanding and exciting field of ferroptosis research.

One third of all proteins in eukaryotes transit between the endoplasmic reticulum (ER) and the Golgi to reach their functional destination inside or outside of the cell. During export, secretory proteins concentrate at transitional zones of the ER known as ER exit sites, where they are packaged into transport carriers formed by the highly conserved coat protein complex II (COPII). Despite long-standing knowledge of many of the fundamental pathways that govern traffic in the early secretory pathway, we still lack a complete mechanistic model to explain how the various steps of COPII-mediated ER exit are regulated to efficiently transport diverse cargoes. In this Review, we discuss the current understanding of the mechanisms underlying COPII-mediated vesicular transport, highlighting outstanding knowledge gaps. We focus on how coat assembly and disassembly dictate carrier morphogenesis, how COPII selectively recruits a vast number of cargo and cargo adaptors, and finally discuss how COPII mechanisms in mammals might have adapted to enable transport of large proteins.

DNA end resection is a crucial early step in most DNA double-strand break (DSB) repair pathways. Resection involves the nucleolytic degradation of 5′ ends at DSB sites to generate 3′ single-stranded DNA overhangs. The first, short-range resection step is catalysed by the nuclease MRE11, acting as part of the MRE11–RAD50–NBS1 complex. Subsequent long-range resection is catalysed by the nucleases EXO1 and/or DNA2. Resected DNA is necessary for homology search and the priming of DNA synthesis in homologous recombination. DNA overhangs may also mediate DNA annealing in the microhomology-mediated end-joining and single-strand annealing pathways, and activate the DNA damage response. By contrast, DNA end resection inhibits DSB repair by non-homologous end-joining. In this Review, we discuss the importance of DNA end resection in various DSB repair pathways, the molecular mechanisms of end resection and its regulation, focusing on phosphorylation and other post-translational modifications that control resection throughout the cell cycle and in response to DNA damage.