More Like this

1. TRIP13 protects pancreatic cancer cells against intrinsic and therapy-induced DNA replication stress

   https://doi.org/10.1093/narcan/zcaf009  

   Anand, Jay R; Droby, Gaith N; Joseph, Sayali; Patel, Urvi; Zhang, Xingyuan; Klomp, Jeffrey A; Der, Channing J; Purvis, Jeremy E; Wolff, Samuel C; Bowser, Jessica L; et al (January 2025, NAR Cancer)

   Abstract Oncogene activation in normal untransformed cells induces DNA replication stress and creates a dependency on DNA damage response (DDR) mechanisms for cell survival. Different oncogenic stimuli signal via distinct mechanisms in every cancer setting. The DDR is also pathologically reprogrammed and deployed in diverse ways in different cancers. Because mutant KRAS is the driver oncogene in 90% of pancreatic ductal adenocarcinomas (PDACs), here we have investigated DDR mechanisms by which KRAS-induced DNA replication stress is tolerated in normal human pancreatic epithelial cells [human pancreatic nestin-expressing (HPNE) cells]. Using a candidate screening approach, we identify TRIP13 as a KRASG12V-induced messenger RNA that is also expressed at high levels in PDAC relative to normal tissues. Using genetic and pharmacological tools, we show that TRIP13 is necessary to sustain ongoing DNA synthesis and viability specifically in KRASG12V-expressing cells. TRIP13 promotes survival of KRASG12V-expressing HPNE cells in a homologous recombination (HR)-dependent manner. KRASG12V-expressing HPNE cells lacking TRIP13 acquire hallmark HR deficiency phenotypes, including sensitivity to inhibitors of translesion synthesis and poly-ADP ribose polymerase. Established PDAC cell lines are also sensitized to intrinsic DNA damage and therapy-induced genotoxicity following TRIP13 depletion. Taken together, our results expose TRIP13 as an attractive new and therapeutically tractable vulnerability of KRAS-mutant PDAC. 

   more » « less
2. An ancient origin of the naked grains of maize

   https://doi.org/10.1073/pnas.2503748122  

   Fairbanks, Regina A; Ross-Ibarra, Jeffrey (June 2025, Proceedings of the National Academy of Sciences)

   Adaptation to novel environments requires genetic variation, but whether adaptation typically acts upon preexisting genetic variation or must wait for new mutations remains a fundamental question in evolutionary biology. Selection during domestication has been long used as a model to understand evolutionary processes, providing information not only on the phenotypes selected but also, in many cases, an understanding of the causal loci. For each of the causal loci that have been identified in maize, the selected allele can be found segregating in natural populations, consistent with their origin as standing genetic variation. The sole exception to this pattern is the well-characterized domestication locustga1(teosinte glume architecture1), which has long been thought to be an example of selection on a de novo mutation. Here, we use a large dataset of maize and teosinte genomes to reconstruct the origin and evolutionary history oftga1. We first estimated the age oftga1-maizeusing a genealogy-based method, finding that the allele arose approximately 42,000 to 49,000 y ago, predating the beginning of maize domestication. We also identifytga1-maizein teosinte populations, indicating that the allele can survive in the wild. Finally, we compare observed patterns of haplotype structure and mutational age distributions neartga1with simulations, finding that patterns neartga1in maize better resemble those generated under simulated selective sweeps on standing variation. These multiple lines of evidence suggest that maize domestication likely drew upon standing genetic variation attga1and cement the importance of standing variation in driving adaptation during domestication. 

   more » « less
3. Genetic diversification of Pseudomonas fluorescens maintained by multi-niche selection within biofilms

   https://doi.org/10.1128/aem.02499-25  

   Matela, Abigail M; Siatkowski, Colton W; Yan, Changhua; Thiagarajan, Sachin; Nawrocki, Erin M; Cooper, Vaughn S (April 2026, Applied and Environmental Microbiology)

   Rudi, Knut (Ed.)

   ABSTRACT We established a research-education partnership, EvolvingSTEM, that currently provides thousands of secondary school students the opportunity to conduct authentic research experiments centered on microbial evolution each year. Providing high school students access to research experiences improves learning, can have positive and long-lasting impacts on their attitudes toward science, and gives them the opportunity to make impactful scientific contributions. Through EvolvingSTEM, students evolve populations ofPseudomonas fluorescensin a bead model that includes daily cycles of bacterial dispersal, attachment, and biofilm growth, and observe heritable changes in colony morphology. We sequenced the genomes of 69 evolved clones with unique colony morphologies and identified parallel mutations in genes known to regulate or affect biofilm growth (wsp,yfiBNR,morA,andfuzY). We also uncovered novel adaptations: loss-of-function mutations in phosphodiesterase PFLU0185 that did not alter colony morphology and mutations affecting periplasmic disulfide bond formation producing small colonies. PFLU0185 mutants rapidly and consistently reached high frequencies, and phenotyping revealed roles in cyclic di-GMP regulation, biofilm formation, and motility, prompting us to name this genebmo(biofilm andmotility regulator). Competition experiments and microscopy demonstrated thatbmomutants are ecological generalists that compete with their ancestor and specialist mutants. Consequently, phenotypic diversity is maintained, with smooth (ancestral andbmo) colonies consistently outnumbering wrinkly and fuzzy variants. This study advances our understanding of biofilm genetic architecture while demonstrating that student-led research can uncover mechanisms of microbial adaptation relevant toPseudomonasinfection biology. IMPORTANCEBacterial biofilms dominate microbial life; however, their evolutionary genetics remain incompletely understood. Extensive replication of biofilm selection experiments by secondary school students can provide valuable insights into mechanisms of adaptation. Notably, mutations in a conserved phosphodiesterase, PFLU0185/bmo, dominate evolved populations without changing colony morphology. Phenotypic assays reveal thatbmoplays a generalist role and competes with its ancestor and other diverse, less frequent biofilm-specialist mutants, resulting in populations that have differentiated to fill multiple niches within the biofilm life cycle. This work also demonstrates the power of distributed research networks for addressing complex biological questions while promoting scientific literacy to the public. 

   more » « less
4. Evolutionary histories of functional mutations during the domestication and spread of japonica rice in Asia

   https://doi.org/10.1073/pnas.2514614122  

   Alam, Ornob; Gutaker, Rafal; Surya, Niketh; Castillo, Cristina; Fuller, Dorian; Guedes, Jade d’Alpoim; Purugganan, Michael (October 2025, Proceedings of the National Academy of Sciences)

   Rice (Oryza sativa) was first domesticated beginning ~9,000 y ago in China as thejaponicavariety group/subspecies. Using genomic data from 456japonicalandraces, including data for 47 herbarium specimens collected over the last 167 y, we reconstruct howjaponicarice moved from its center of origin to other parts of Asia beginning ~4,000 to 5,500 y ago. We observe an enrichment of pathogen resistance loci in selective sweeps associated with distinct geographic populations, suggesting that biotic interactions may be a key driver of local adaptation. We also find that the majority of 76 known functional mutations present in ourjaponicalandraces—many of them associated withjaponicarice domestication and diversification and important for modern breeding—had their origins in the Pleistocene >11,700 y ago and increased in allele frequency during key events in the evolution of rice. 

   more » « less
5. Diel expression dynamics in filamentous cyanobacteria

   https://doi.org/10.1128/mbio.03779-24  

   Kennedy, Sarah J; Risser, Douglas D; Paul, Blair G (December 2025, mBio)

   Davis, Kimberly M (Ed.)

   ABSTRACT Filamentous cyanobacteria of theNostocaceaefamily can differentiate into multicellular forms to adapt to environmental stresses, and members can establish symbiosis with various embryophytes. Representative laboratory strains are typically grown under continuous light to maintain stable metabolic conditions; however, this departure from a natural diel cycle can result in extended stress. Early genomic examination ofNostoc punctiformesuggests the genetic potential for a circadian clock, but we lack insight into global cellular dynamics through the natural diel cycle for this model organism. Here, we comprehensively assess changes in expression of core cellular processes and the mobilome of accessory genetic elements during diel growth ofN. punctiformePCC 73102. The primary transcriptome confirmed that multicellular cyanobacteria precisely coordinate photosynthesis and carbon assimilation for cell division during the day, while control of DNA recombination and repair appeared to be sequestered to darkness. Moreover, we expanded the known repertoire of light-sensing proteins to uncover a putative regulator of circadian rhythm that itself exhibits striking oscillation between day-night expression. This was in sharp contrast to the arrhythmic pattern observed for a homolog of the canonical circadian input kinase in unicellular cyanobacteria. Looking beyond cellular coordination of diel growth, we uncovered dynamic mobile elements and, notably, targeted hypermutation by retroelements that are likely maintained for conflict mitigation, which is crucial for a multicellular lifestyle.IMPORTANCEModel strains of filamentous cyanobacteria are typically cultivated under controlled laboratory conditions that poorly reflect the natural environment, including growth under constant light. Our study addresses this discrepancy to provide a new benchmark for investigating gene expression in the model organism,Nostoc punctiforme. By analyzing changes in the global transcriptome over a diel cycle, we found a clear partition of cellular processes between periods of light and darkness, with metabolism dominating in the light and cell maintenance and repair processes dominating in the dark. In addition, an active mobilome of genetic elements was uncovered with dynamic expression patterns throughout a diel cycle. Our findings highlight the importance of considering diel cycles in cyanobacterial research and provide new insight into the regulatory complexity, genome plasticity, and adaptive mechanisms of these ecologically important organisms. Our study reinforces the need to consider the natural diel cycle in laboratory models of filamentous cyanobacteria, bringing new insights into their regulatory complexity and revealing adaptive drivers of genome plasticity that may enable members ofNostocto occupy a wide variety of ecosystems. 

   more » « less