Trends in Biochemical Sciences最新文献

Methionine metabolism is canonically linked to gene regulation through S-adenosylmethionine (SAM)-dependent methylation of RNA. Recently, Liao et al. revealed a SAM-independent mechanism wherein adenosylhomocysteinase-adenosine complex modulates fat-mass and obesity-associated protein (FTO), reshapes the mRNA m⁶A landscape, rewires lipid metabolism, and promotes tumorigenesis, revealing a novel metabolic-epitranscriptomic cancer axis.

Adenosine Monophosphate (AMP)-activated protein kinase (AMPK) is a critical kinase in the control of cellular metabolism, and in recent years, accumulating evidence has demonstrated that AMPK plays a critical role in the regulation of various types of regulated cell death (RCD) pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. In this review, we will first discuss the regulatory roles of AMPK in these forms of RCD. Then, we will examine the implications of AMPK in diseases such as cancer, diabetes complications, ischemia-reperfusion injury, and infectious diseases, focusing on the therapeutic potential of AMPK activators and inhibitors through the regulation of different types of RCD.

Post-translational modifications (PTMs) can regulate the localization, function, and activity of proteins. Different PTMs can influence each other to create complex regulatory networks with significant implications for cellular signaling and protein homeostasis; an interplay known as crosstalk. Here, we highlight recent studies revealing crosstalk between ubiquitination and ADP-ribosylation, two PTMs that, while chemically distinct, share notable mechanistic similarities. We discuss how their enzymes, substrates, and resulting adducts are similar and distinct. We describe the different levels at which one PTM impacts the other and, ultimately, how they build on each other to create a hybrid modification. Both ADP-ribosylation and ubiquitination are targeted by drugs, and understanding this crosstalk is also important for translational research, opening potentially innovative strategies for new therapies.

Recent work by Wang and colleagues reveals a unique mode of cell death called mitoxyperilysis, driven by mitochondrial proximity-dependent rupture of the plasma cell membrane. This lytic cell death is triggered by immune agonists combined with fasting or nutrient starvation, offering therapeutic implications in sepsis and cancer.

Bacteria and archaea acquire immune memories by integrating foreign DNA into clustered regularly interspaced short palindromic repeats (CRISPR) arrays. Zhou et al. reveal that Cas9-thought to act only with guide RNAs-also functions in its RNA-free form, stimulating spacer acquisition. Rising CRISPR RNA levels shift the equilibrium toward the RNA-bound state, attenuating acquisition and minimizing autoimmunity.

Interpreting variants of uncertain significance remains a central challenge in human genomics. Base and prime editors have launched a new era of precision functional genomics, enabling programmable, double-strand break-free introduction of point mutations and small indels directly within the genome. Here, we review the technological evolution of these editors and their transformative application in high-throughput functional screens. We highlight how base and prime editing platforms systematically annotate clinical variants, reveal mechanisms of drug resistance and immune evasion, and dissect fundamental biological processes at single-nucleotide resolution. Crucially, we address current challenges and future perspectives for precision editing screens. By enabling causal genotype-to-phenotype mapping, precision editing screens are redefining genomic variation interpretation and accelerating its translation into precision diagnostics and therapeutics.

Cellular metabolic pathway reconstruction is an essential yet challenging goal in synthetic biology. We outline a conceptual framework integrating retrosynthetic planning with biological constraints to enhance biological feasibility. We believe the approach spans individual- and systems-level modeling, enabling large language model-driven understanding, design, evaluation, and optimization of metabolic networks.

Programmed DNA double-strand breaks (DSBs) catalyzed by the conserved topoisomerase-like complex SPO11-TOP6BL, together with its accessory proteins, initiate meiotic recombination, a process central to meiosis. In mammals, DSBs are distributed nonrandomly at preferential genomic sites (called hotspots) defined largely by the meiosis-specific protein PRDM9. Precise temporal and spatial control of DSB formation is essential for generating genetic diversity while maintaining genomic stability during meiosis. Disruption of this process leads to aberrant recombination, chromosome mis-segregation, and reproductive defects. In this review, we summarize recent genetic, biochemical, and structural advances clarifying the molecular architecture and regulation of meiotic DSB formation in mammals.

Superfamily 1 helicases are conserved nonhexameric ATP-dependent enzymes that unwind DNA and RNA duplexes processively or remove proteins, playing critical roles in DNA repair, replication, recombination, and RNA processing. While crystal structures of Superfamily 1A UvrD-family helicases suggested that monomers are active helicases requiring an essential 2B regulatory domain-DNA interaction, biochemical studies show that helicase activation requires dimerization. Recent cryo-electron microscopy (EM) structures of Mycobacterium tuberculosis UvrD1 dimers reveal that dimerization involves the 2B domains, eliminating their inhibitory interaction with duplex DNA, contradicting these original models. Escherichia coli UvrD dimers use the same dimerization interface, suggesting a general mechanism for this class of helicases. Herein, we describe how these results require re-evaluation of helicase mechanisms that were based on the monomeric structures alone.

Transcriptional responses are initiated immediately after the recognition of pathogen-associated molecular patterns by pattern recognition receptors, enabling host cells to deal with inflammatory stimuli, including microbial infections. In turn, these inflammatory transcriptional programs must be tightly controlled to prevent potential detrimental consequences, such as immunopathological or even fatal outcomes. To date, many well-defined mechanisms have been reported that contribute to the transcriptional control of inflammatory gene expression at multiple levels. Here, I mainly focus on reviewing recent progress in post-translational modifications, in particular, how the ubiquitination-deubiquitination cycle controls inflammatory gene transcription mediated by nuclear factor kappa-light-chain-enhancer of activated B cells and interferon signaling pathways. Lastly, I will emphasize the importance of understanding gene-specific mechanisms in controlling inflammatory gene transcription.