Mammalian cells frequently enter mitosis before DNA replication has finished, necessitating the rapid processing of unreplicated loci to facilitate chromosome segregation. The TRAIP ubiquitin ligase induces replisome dis...Mammalian cells frequently enter mitosis before DNA replication has finished, necessitating the rapid processing of unreplicated loci to facilitate chromosome segregation. The TRAIP ubiquitin ligase induces replisome disassembly during mitosis, triggering the cleavage of DNA replication forks. Until now, the mechanisms that regulate TRAIP and process cleaved DNA replication forks were unclear. Here we show that the TTF2 ATPase is a new type of phospho-receptor that binds a conserved phosphorylation site on TRAIP during mitosis. TTF2 couples phosphorylated TRAIP to DNA polymerase epsilon (Pol ε) in the replisome, leading TRAIP to ubiquitylate the CDC45-MCM-GINS (CMG) helicase. This triggers mitotic replisome disassembly, and a repair pathway that produces sister-chromatid exchanges, supporting a model for how fork cleavage promotes the segregation of under-replicated loci in mammalian cells.
Thalamocortical projections shape the functional regionalization and parallel sensory computations across the mammalian cortex. However, the principles of thalamocortical computations in non-mammalian vertebrates remain...Thalamocortical projections shape the functional regionalization and parallel sensory computations across the mammalian cortex. However, the principles of thalamocortical computations in non-mammalian vertebrates remain underexplored. Here we investigated how the zebrafish pallium, a homolog of the vertebrate cortex, receives and processes sensory information, and how its architecture compares to thalamocortical circuits in other vertebrates. We revealed that the preglomerular complex (PG), a thalamocortical-like pathway, is the primary source of visual and vibrational information to the zebrafish pallium. PG and its pallial projections exhibit sensory-specific and topographically organized responses. In contrast, pallial neurons display topographically organized hierarchies, ranging from sensory-specific to multimodal and coincidence-detecting nonlinear responses. Our results suggest that hierarchies of sensory transformations across topographically organized thalamocortical-like circuits reflect a convergent principle across vertebrates.
Can G, Shyian M, Krishnamoorthy A
… +11 more, Ahmed S, Lim Y, Wu A, Pavani R, Zaher MS, Nussenzweig A, Räschle M, Wilson TE, Glover TW, Walter JC, Pellman D
Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork...Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a -acting to a -acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: the ATPase TTF2 is recruited to the replisome, where its noncatalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.
Wiesbeck M, Alard EL, Merino F
… +22 more, Chowdhury N, Egert L, Danese A, Imhof S, Iraci Borgia M, Rajan A, Fernandez-Novel Marx N, Kepesidis E, Köferle A, Cerron-Alvan LM, Vierl F, Truong TT, Thorwirth M, Bilalli L, Ninkovic J, Schieweck R, Diefenbacher M, Hauck SM, Trainor P, Mardakheh FK, Götz M, Stricker SH
Ribosomal RNA (rRNA) transcription rates vary during development, and their dysregulation is linked to diseases such as cancer and ribosomopathies. Owing to their high abundance and genomic redundancy, the functional sig...Ribosomal RNA (rRNA) transcription rates vary during development, and their dysregulation is linked to diseases such as cancer and ribosomopathies. Owing to their high abundance and genomic redundancy, the functional significance of rRNA-levels remains unclear. Here, we developed TAPIR (Targeted Activation of Protein Translation), a CRISPR-based approach to elevate rRNA-levels by inducing 47S rDNA transcription. TAPIR increased nucleolar size and enhanced protein synthesis, even in rapidly proliferating cells. In neural stem cells, elevated translation promoted self-renewal and proliferation in vitro and in vivo. Furthermore, TAPIR enabled the modeling and partial rescue of associated disease phenotypes. Our findings revealed that rRNA-levels directly regulate translational output and that protein synthesis capacity can act as a key determinant of mammalian stem cell behavior.
Martian rocks are known to contain sulfur-bearing species, including sulfates and sulfides. These compounds record a sulfur cycle that operated over Mars' geological evolution. We used the Curiosity rover to investigate...Martian rocks are known to contain sulfur-bearing species, including sulfates and sulfides. These compounds record a sulfur cycle that operated over Mars' geological evolution. We used the Curiosity rover to investigate a deposit of light-toned stones in Gediz Vallis, within Gale crater on Mars. We find that the stones are composed of native sulfur. The sulfur deposit appears to have formed in place, within a sinuous entrenched canyon cut into the floor of Gediz Vallis. The presence of native sulfur implies that a sulfur enrichment pathway involving buoyant subsurface fluids operated on ancient Mars. We propose that the primary source of this sulfur was magmatic vapor, which cooled in the near subsurface cryosphere and was released by decompression during the erosion of Gediz Vallis.
Iron-mediated programmed cell death spreads through colonies of toxic cyanobacteria.Iron-mediated programmed cell death spreads through colonies of toxic cyanobacteria.
The physiological state of neurons controls the expression of gene variants linked with psychiatric disease.The physiological state of neurons controls the expression of gene variants linked with psychiatric disease.
Lariat RNAs are formed from introns during pre-messenger RNA splicing, after which they are degraded by the debranching enzyme DBR1. Impairment of DBR1 leads to developmental arrest, yet the mechanism remains unclear. In...Lariat RNAs are formed from introns during pre-messenger RNA splicing, after which they are degraded by the debranching enzyme DBR1. Impairment of DBR1 leads to developmental arrest, yet the mechanism remains unclear. In this study, we found that debranching of lariat RNA prevents production of 21- and 22-nucleotide lariat-derived small interfering RNAs (lasiRNAs), which causes a burst of exonic siRNAs, thereby safeguarding development and defense response. LasiRNA biogenesis relied on RNA-dependent RNA polymerases and Dicer-like proteins (DCLs). Upon pathogen infection and dysfunction of DBR1, many lariat RNAs were hijacked by DCL4 and DCL2 and processed into siRNAs that particularly target immunity genes, ultimately disrupting plant defense responses. Collectively, DBR1-mediated lariat RNA removal serves as a protective mechanism to prevent the activation of a small RNA-based defense system in plants.
Angiosperm reproductive evolution is traditionally linked to the end-Cretaceous biotic crisis and subsequent ecological restructuring. Here, we report diverse and unexpectedly large diaspores (dispersal units) from an in...Angiosperm reproductive evolution is traditionally linked to the end-Cretaceous biotic crisis and subsequent ecological restructuring. Here, we report diverse and unexpectedly large diaspores (dispersal units) from an in situ late Campanian (74.6 million years ago) tropical forest from the Jose Creek Formation in New Mexico. Nearly 80 distinct diaspore morphotypes demonstrate that the flora had increased morphological specialization and an exceptionally large average and range of diaspore volume comparable to the Cenozoic records. These findings suggest that substantial increases in reproductive investment and specialization preceded the end-Cretaceous extinction. Our results indicate that Cretaceous angiosperms had already evolved diverse dispersal strategies, suggesting that animal-mediated dispersal and dense, angiosperm-integrated canopies were established far earlier than was previously recognized.
Fossil proteins show 20 members of an extinct human species found in a South African cave were female.Fossil proteins show 20 members of an extinct human species found in a South African cave were female.
Imagine an American organization that convenes scientific experts not to advance any ideology or interest but to provide the nation with a clear understanding of complex problems. Imagine this body would follow the evide...Imagine an American organization that convenes scientific experts not to advance any ideology or interest but to provide the nation with a clear understanding of complex problems. Imagine this body would follow the evidence rather than the headlines and earn its authority not through rhetoric or persuasion but careful and rigorous analysis and transparent processes. This institution exists-although its work faces pressing challenges-and it is more urgently needed today than at any point in living memory.
Wen AX, Bos J, Panda D
… +13 more, Hagstrom KM, Singh S, Mageswaran SK, Wang X, Hu B, Welch KT, Cooke MB, Halliday JA, Deus Ramirez L, Martinez AE, Chang YW, Weitz DA, Herman C
The exchange of biological matter between bacterial cells drives adaptation and evolution. However, whether bacteria can exchange functional proteins remains unclear. In this work, we found that antibiotic treatment can...The exchange of biological matter between bacterial cells drives adaptation and evolution. However, whether bacteria can exchange functional proteins remains unclear. In this work, we found that antibiotic treatment can induce vesicle-mediated horizontal protein transfer within and between bacterial species. We developed a genetic system in to track transfer events and performed single-cell transcriptomic profiling on an isogenic population of bacteria. Antibiotics stimulated the differentiation of this isogenic population into distinct cell states: donor cells that activated a membrane stress response to release protein-containing vesicles and recipient cells that suppressed this response to acquire protein from their neighbors. Protein uptake enhanced the antibiotic persistence of recipient cells, revealing that vesicle exchange promotes bacterial survival during antibiotic treatment.
Photopic vision, including fast motion and color perception in daylight, is mediated by cone opsins, specialized G protein-coupled receptors (GPCRs). Despite sharing the same chromophore, the three receptor subtypes abso...Photopic vision, including fast motion and color perception in daylight, is mediated by cone opsins, specialized G protein-coupled receptors (GPCRs). Despite sharing the same chromophore, the three receptor subtypes absorb light at different wavelengths of the visible spectrum. The molecular mechanisms governing their spectral properties and exceptionally rapid responses remain largely unknown. We report cryo-electron microscopy structures of the human blue-sensitive (OPN1SW) and green-sensitive (OPN1MW) cone opsins in their dark-adapted states, combined with femtosecond-resolution spectroscopy, functional assays, and advanced simulations. The data reveal distinct chromophore stabilization mechanisms across human visual opsins and specific sequence adaptations in the GPCR microswitch motifs, underlining their structural plasticity and distinct activation mechanisms. These findings delineate the molecular basis of the evolutionary refinements fulfilling the needs of vision in daylight.