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Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas

(Cell Reports 32, 108196; September 29, 2020)

As this paper was originally published on September 29, 2020, Figure 3C showed similar imagery across western blot analyses for αTubulin and pAkt473. This error was caused by an inadvertent swap of two loading control panels of αTubulin and Akt that appeared during figure assembly. The corrected figure can be seen below.

The error and correction thereof do not affect the results or conclusions of the study. The authors apologize for any confusion caused.

CPSF73 activation and 3′ RNA polymerase II pausing are lost during readthrough transcription after heat shock

Here, we identified key signatures of transcriptional termination mechanisms that are altered by heat shock, enabling global readthrough of the 3′ends of mRNA genes. The Pol II 3′ pause is lost, CTD phosphorylation at Ser2 and Tyr1 changes, and endonucleolytic cleavage of the transcript is impaired, which is relieved by expression of RBBP6, a cleavage activator. Our data support a multifaceted mechanism of readthrough during stress, whereby changes to both Pol II and the termination machinery trigger transcription to bypass normal termination sites.

The stress-induced readthrough we observed was pervasive, with 85% of the analyzable genes showing downstream transcription after heat shock. There was no correlation with the level of transcription or activation/repression and no indication of any gene class specificity. Prior work has shown that genes with readthrough are largely overlapping between types of cellular stress.19 Moreover, only loose correlations have been found between sequence markers for termination, such as the strength of the PAS and/or flanking GA-rich regions, and readthrough transcription.26 Distinguishing characteristics of readthrough susceptibility for any given stress remain to be elucidated.

Our Pol II ChIP-seq data show that heat shock induces global loss of 3′ Pol II pausing. This occurred at genes with and without readthrough, indicating that lack of Pol II pausing is not sufficient to cause readthrough. This raises interesting questions about the relationship between Pol II deceleration and transcription termination mechanisms. Current models suggest the slowing of Pol II helps the 5′-to-3′ exonuclease XRN2 to degrade the nascent RNA, catch up to transcribing Pol II, and trigger the dissociation of the polymerase from the DNA.9,10,34 This model requires that nascent RNA cleavage occurs to generate the 5′ end for XRN2 to bind. For readthrough genes that retain RNA cleavage during heat shock, the failure of Pol II to decelerate could prevent XRN2 from “catching up,” thereby enabling downstream transcription. For readthrough genes that lose cleavage, Pol II deceleration likely enhances readthrough by having a fast-moving polymerase.

Senescence at the crossroads of postpartum remodeling and tumorigenesis

Cellular senescence has been linked to both beneficial and detrimental functions. Chiche, Djoual, Charifou and colleagues show that senescence supports normal postpartum mammary gland remodeling, but that when oncogenic events coincide with involution, senescent cells enhance tumorigenesis by regulating plasticity, invasion and metastasis.

AI Designed Peptides Could Cure… EVERYTHING. LigandForge Is Here

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A man with no medical background used ChatGPT, AlphaFold, and Grok to design a custom mRNA cancer vaccine for his dying dog — and her biggest tumor shrank 75%.

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In this deep dive, I break down how these three breakthroughs fit together, what peptides and mRNA vaccines actually are (and how they’re different), and why this moment might be the most important inflection point in the history of drug design.

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Continue reading “AI Designed Peptides Could Cure… EVERYTHING. LigandForge Is Here” | >

Ancient DNA finds 15,800-year-old dogs in Anatolia, buried like humans

Evidence of some of the earliest dogs has been identified at two University of Liverpool/British Institute at Ankara archaeological excavation projects in central Anatolia, Turkey. Shedding new light on the development and spread of early domestic dogs, the findings are documented in two papers published in Nature.

Providing fascinating insights into dogs’ relationships with people and their rapid spread across Europe and Anatolia, the work involved zooarchaeologists from University College London, University of Liverpool and based in Turkey and ancient DNA and isotope teams from the Natural History Museum, the Universities of Oxford and York, the Francis Crick Institute, and LMU Munich.

Two of the key excavation sites used are led by the University of Liverpool’s Professor Douglas Baird—Pınarbaşı excavated with Karaman museum and Boncuklu excavated with co-directors Professor Fairbairn, University of Queensland and Associate Professor Mustafaoĝlu, Ankara Hacı Bayram Veli University. Together, the sites span the transition from the Epipaleolithic (latest Paleolithic) to early Neolithic dated 16,000 to 10,000 years ago.

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