Biology subjects

Tomasini, M.

Publications and source records attributed to Tomasini, M..

6 recordsLinked to original sources

bioRxiv2025

Specific degrader for fusion oncokinase kills tumors and is augmented by bimodal degrader-siRNA

Oncogenic fusions of two native proteins are challenging to block without disturbing the parental proteins. A mRNA delivered peptide degrader, selectively eliminates the oncogenic fusions DNAJB1::PRKACA and ATP1B1::PRKACA in fibrolamellar carcinoma (FLC), cholangiocarcinoma and intraductal pancreatic neoplasm, without effect on native PRKACA. Specific degradation reflected structural properties of the fusion proteins. The degrader was lethal to FLC tumor cells in a preclinical model, with no effect on non-FLC cells. To enhance efficacy and speed, we modified the mRNA to simultaneously encode the degrader and an siRNA against the fusion transcript, reducing new protein synthesis which accelerated degradation of DNAJB1::PRKACA, offering a wide therapeutic index for mutation-driven disease.

cancer biology↗

bioRxiv2022

Species' ranges and the steepening-gradient hypothesis

One hypothesis invoked to explain limits to species ranges is a mismatch in environmental conditions between the central and marginal areas of species ranges. Low population size at the margins causes genetic drift to outplay selection locally, and limits the accumulation of genetic variance, so that adaptation is hindered locally. Earlier theoretical work shows that, for a population expanding over a spatially heterogeneous environment without any geographical barriers, adaptation will fail abruptly and sharp range margins will establish only when the underlying environmental conditions change more and more severely across space, whereas an environment changing constantly will result either in infinite expansion or rapid global extinction. Here, we extend this "steepening-gradient hypothesis" to encompass situations when multiple (up to three) environmental factors impose selection on separate adaptive traits. We show that multiple selection gradients steepen each other and that it is sufficient that just one of the gradients steepen in space for sharp range margins to form. This is true even if this gradient is shallow throughout the realised range. Thus, despite its detrimental role in forming range margins, it could be overlooked in field studies. Finally, by decomposing an environmental gradient to selection on two (or three) adaptive traits, we show that a population can withstand harsher environmental conditions than when selection acts on one adaptive trait alone. This finding argues for the evolution of novel traits in harsh environments.

evolutionary biology↗

bioRxiv2020

Fragmentation helps evolutionary rescue in highly connected habitats

Genetic variation and population sizes are critical factors for successful adaptation to novel environmental conditions. Gene flow between sub-populations is a potent mechanism to provide such variation and can hence facilitate adaptation, for instance by increasing genetic variation or via the introduction of beneficial variants. On the other hand, if gene flow between different habitats is too strong, locally beneficial alleles may not be able to establish permanently. In the context of evolutionary rescue, intermediate levels of gene flow are therefore often optimal for maximizing a species chance for survival in metapopulations without spatial structure. To which extent and under which conditions gene flow facilitates or hinders evolutionary rescue in spatially structured populations remains unresolved. We address this question by studying the differences between evolutionary rescue in the island model and in the stepping stone model in a gradually deteriorating habitat. We show that evolutionary rescue is modulated by the rate of gene flow between different habitats, which in turn depends strongly on the spatial structure and the pattern of environmental deterioration. We use these insights to show that in many cases spatially structured models can be translated into a simpler island model using an appropriately scaled effective migration rate.

molecular biology↗

bioRxiv2019

When does gene flow facilitate evolutionary rescue?

AO_SCPLOWBSTRACTC_SCPLOWExperimental and theoretical studies have highlighted the impact of gene flow on the probability of evolutionary rescue in structured habitats. Mathematical modelling and simulations of evolutionary rescue in spatially or otherwise structured populations showed that intermediate migration rates can often maximize the probability of rescue in gradually or abruptly deteriorating habitats. These theoretical results corroborate the positive effect of gene flow on evolutionary rescue that has been identified in experimental yeast populations. The observations that gene flow can facilitate adaptation are in seeming conflict with traditional population genetics results that show that gene flow usually hampers (local) adaptation. Identifying conditions for when gene flow facilitates survival chances of populations rather than reducing them remains a key unresolved theoretical question. We here present a simple analytically tractable model for evolutionary rescue in a two-deme model with gene flow. Our main result is a simple condition for when migration facilitates evolutionary rescue, as opposed as no migration. We further investigate the roles of asymmetries in gene flow and / or carrying capacities, and the effects of density regulation and local growth rates on evolutionary rescue.

evolutionary biology↗

bioRxiv2018

Structures of the PKA RIα holoenzyme with the FLHCC driver J-PKAcα or wild type PKAcα

Fibrolamellar hepatocellular carcinoma (FLHCC) is driven by J-PKAc, a kinase fusion chimera of the J-domain of DnaJB1 with PKAc, the catalytic subunit of Protein Kinase A (PKA). Here we report the crystal structures of the chimeric fusion RI2:J-PKAc2 holoenzyme formed by J-PKAc and the PKA regulatory (R) subunit RI, and the wild type (wt) RI2:PKAc2 holoenzyme. The chimeric and wt RI holoenzymes have quaternary structures different from the previously solved wt RI{beta} and RII{beta} holoenzymes. The chimeric holoenzyme shows an isoform-specific interface dominated by antiparallel interactions between the N3A-N3A motifs of RI that serves as an anchor for RI structural rearrangements during cAMP activation. The wt RI holoenzyme showed the same configuration as well as a distinct second conformation. In the structure of the chimeric fusion RI2:J-PKAc2 holoenzyme, the presence of the J-domain does not prevent formation of the holoenzymes, and is positioned away from the symmetrical interface between the two RI:J-PKAc heterodimers in the holoenzyme. The J-domains have significantly higher temperature factors than the rest of the holoenzyme, implying a large degree of conformational flexibility. Furthermore molecular dynamics simulations were applied to analyze the conformational states of chimeric fusion and wt RI holoenzymes, and showed an ensemble of conformations in the majority of which the J-domain was dynamic and rotated away from the R:J-PKAc interface. Thus, rather than affecting the interactions with the regulatory subunits, the fusion of the J-domain to the PKAc alters the conformational landscape of the chimeric fusion holoenzymes and potentially, as result, the interactions with other molecules. The structural and dynamic features of these holoenzymes enhance our understanding of the fusion chimera protein J-PKAc that drives FLHCC as well as the isoform specificity of PKA.

biochemistry↗

bioRxiv2018

Establishment of locally adapted mutations under divergent selection

We study the establishment probabilities of locally adapted mutations using a multitype branching process framework. We find a surprisingly simple and intuitive analytical approximation for the establishment probabilities in a symmetric two-deme model under the assumption of weak (positive) selection. This is the first analytical closed-form approximation for arbitrary migration rate to appear in the literature. We find that the establishment probability lies between the weak and the strong migration limits if we condition the origin of the mutation to the deme where it is advantageous. This is not the case when we condition the mutation to first occur in a deme where it is disadvantageous. In this case we find that an intermediate migration rate maximizes the probability of establishment. We extend our results to the cases of multiple demes, two demes with asymmetric rates of gene flow, and asymmetric carrying capacities. The latter case allows us to illustrate how density regulation can affect establishment probabilities. Finally we use our results to investigate the role of gene flow on the rate of local adaptation and identify cases in which intermediate amounts of gene flow facilitate the rate of local adaptation as compared to two populations without gene flow.

evolutionary biology↗