Presentation Order:
Alyssa
Hannah
Shah
Keaton
Time: biweekly, Wednesday 9:30-11:50
Writing 9:30-10:00---5-10 min/person
Research Presentation: 30 minutes talk+discussion
AJM
Genetic elements promote retention of extrachromosomal DNA in cancer cells
Extra-chromosomal DNA (ecDNA) is a prevalent oncogene activator in diverse cancers, permitting heritable additive expression of oncogenes across cell generations. How ecDNA is retained has been well studied in the viral replication context, however, its mechanism in the human genome has not been established. Herein, the authors revealed a novel method, termed Retain-Seq, that sequences transduced plasmids with random human genome inserts to identify retention sequences that allow ecDNA retention across several rounds of cell division. The authors identify diverse retention sequences with a common thread of transcription-activating regions, including transcriptional start sites, promoters, and enhancer. Importantly, these regions are enriched in CpG sites. Given CpG methylation is crucial for promoter activity, the authors tested the impact of differential methylation status of ecDNA’s CpGs on retention, finding decreased ecDNA retention and subsequent cell proliferation and viability with increased CpG methylation. Overall, the authors elucidate an important biological means of oncogene activation that could pose a novel target for therapeutic intervention against cancer, and could be further applied to improve targeted personalized gene therapies in chronic disease.
KK
Atomically accurate de novo design of antibodies with RFdiffusion
Antibodies are critical to immune defense and as a novel therapeutic class; however, de novo development of antibodies to target specific epitopes requires costly and time-consuming in vivo screening. To address this challenge, the authors of this study created a computational framework to design antibodies against clinically relevant epitopes. A set of antibody designs generated with a modified version of their RFdiffusion structure prediction model, yielded several candidate antibodies that bound to the target, though not at the desired affinity. The authors then combined their model with an additional step to mutate the candidate designs in silico, eventually reaching the desired affinity. Although the current implementation of this approach requires more optimization and validation than is practical for most potential end users, it represents a promising innovation toward de novo antibody design.
HL
Secretome translation shaped by lysosomes and lunapark-marked ER junctions
The spatial organization that drives the translation of mRNAs encoding secretory and membrane proteins at the endoplasmic reticulum (ER), and their coordination with other organelles such as lysosomes, remains poorly understood. Using real-time single-molecule imaging, Choi et al. define the spatial relationship between secretome mRNA translation, ER junctions, and lysosomal proximity. They demonstrate that secretome mRNAs associate with the ER during active translation but are more diffuse when untranslated, and that translating mRNAs preferentially localize to ER three-way junctions termed “translation hotspots.” These hotspots are enriched for the ER-shaping protein Lunapark and frequently positioned near lysosomes. Functionally, efficient secretome mRNA translation depends on both Lunapark and intact lysosomal activity, with lysosomal metabolic state modulating local translation such that amino-acid starvation enhances, while lysosomal deacidification suppresses, translation near junctions. Together, these findings identify a novel mechanism in which Lunapark-marked ER junctions and lysosomes spatially coordinate the translation of secretory and membrane protein mRNAs, reframing ER architecture as an active regulator of translational control rather than a passive scaffold.
ST
Neoadjuvant immunotherapy in mismatch-repair-proficient colon cancers