Biology subjects

Fischer, G.

Publications and source records attributed to Fischer, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Climate change and extreme weather events to intensify West Nile virus activity

Vector-borne zoonotic diseases pose a substantive risk to public health worldwide, yet predicting outbreaks at scales useful for public health response remains a critical challenge. Transmitted by Culex mosquitoes, West Nile virus is the leading cause of arboviral disease in the United States, progressing to neuroinvasive disease in approximately 1% of infections. Arizona's record-breaking 2021 outbreak, with 1,715 reported human cases and 127 deaths exemplifies this growing burden. Using a decade of mosquito surveillance data coupled with time-lagged weather patterns in a random forest framework, we developed spatial models predicting Culex abundance and West Nile virus occurrence across Arizona at weekly temporal and fine spatial resolution. Our weighted models classified viral occurrence with 98.9% accuracy and explained 65.3% of weekly variation in county-level human cases, with human cases lagging modeled activity by one week. Neither mosquito abundance nor viral occurrence declined at the extreme temperatures characteristic of Arizona summers, suggesting that thermal refugia sustain transmission. Drought-monsoon cycling, rather than temperature alone, emerged as the primary driver of West Nile activity, and projections through 2100 indicate intensifying activity under all climate change scenarios.

ecology↗

bioRxiv2026

A reproductive hierarchy controls mating fates among sibling yeast gametes

Mating strategies shape inbreeding, gene flow and genetic diversity, yet their outcomes remain challenging to quantify. In Saccharomyces, population-genomic models predict mating predominantly between sibling meiotic products, with rare selfing and outcrossing. Here we developed an integrated framework combining multicolor flow cytometry, time-resolved imaging and mathematical modelling to directly quantify mating across scales. Bulk measurements revealed coexisting strategies whose frequencies vary with density, genotype and environment. A minimal stochastic model uses these population-level patterns to infer probabilistic hierarchies among mating modes, which single-tetrad analyses independently support. These reveal divergent and interdependent reproductive trajectories among sibling gametes, with one pair typically mating first and reshaping opportunities for the others. Temporal heterogeneity in germination and mating further diversifies reproductive outcomes and shapes compatibility, as experimental synchronization overcomes temporal reproductive barriers, enabling hybridization. Together, reproductive strategy emerges from heterogeneous gamete fates, raising the possibility that sibling diversification constitutes reproductive bet-hedging.

genetics↗

bioRxiv2026

DNA:RNA hybrid mutational landscapes reveal a common route to geneticinstability in evolving genomes

Pervasive DNA:RNA hybrids are recognized as pathological sources of genome instability, yet how their genotoxicity shapes mutational landscapes and genome evolution remains poorly understood. Here, we define the mutational footprint of hybrids by integrating genome-wide mapping, long-term mutation accumulation experiments, and analyses of genetic diversity across thousands of natural yeast genomes. We uncover signatures for embedded ribonucleotides and genic R-loops, together with a composite mutational pattern shared across natural populations and experimental evolution. Using reporters designed to dissect the mechanisms underlying genetic alterations, we find that they arise primarily from targeting by MutL{gamma}-dependent mismatch repair followed by Rad52-mediated recombination. Although hybrids form dynamically across the genome, their genotoxicity is strongly skewed toward repetitive regions susceptible to these error-prone pathways, including microsatellites and retroelements. Our findings reveal a common mechanism of hybrid-associated mutagenesis that can shape genetic variation in evolving genomes.

molecular biology↗

bioRxiv2026

A stepwise route to polyploidy in yeast

Polyploidy, the presence of multiple chromosome sets within a genome, is widespread and has played a major role in genome evolution in plants, fungi, and animals. Although polyploidization is generally attributed to mitotic genome doubling or unreduced gamete fusion, the mechanisms underlying ploidy increases, particularly triploid formation, remain unclear. Here, we identify a novel route to autopolyploidization in Saccharomyces cerevisiae, termed Sporulate-Endoreplicate-Mate (SEM), in which one gamete, or spore, undergoes postmeiotic endoreplication and subsequently mates with a nearby non-endoreplicated sibling spore after ascus breakdown, increasing ploidy by one haploid genome. We experimentally demonstrate stepwise transitions from diploidy to triploidy and from triploidy to tetraploidy. Intact asci can spontaneously generate new triploid and tetraploid strains upon one or two successive SEM cycles. Natural polyploids exhibit genomic signatures consistent with SEM being a major natural route to polyploidization in yeast. SEM establishes triploids as central intermediates in yeast polyploidization, analogous to the triploid bridge described in plants, and raises the possibility that a similar mechanism may contribute to polyploid genome formation in other eukaryotes.

genomics↗

bioRxiv2026

Host-shift adaptation shapes genome architecture in S. eubayanus

The host environment can profoundly shape the genome architecture of microbial species, and Saccharomyces eubayanus, the wild progenitor of lager yeast, provides a natural system to study this process. Most populations are associated with Nothofagus trees across Patagonia, whereas related Holarctic strains occur in the Northern Hemisphere and are associated with non-Nothofagus hosts. The evolutionary events leading to the emergence of these northern populations on a novel host remain unclear. Here, we analyzed 471 genomes from eight countries and different hosts, Nothofagus in the Southern Hemisphere and non-Nothofagus tree species in the Northern Hemisphere. Phylogenomic analysis identified eight Patagonian lineages and revealed that Holarctic strains derived from recent admixture among Patagonian ancestors, generating the genomic background of the lager-yeast mother lineage. Long-read assemblies showed that non-Nothofagus-associated strains harbor an elevated burden of structural variants (SVs), particularly in subtelomeric MAL and IMA regions, involved in sugar metabolism. Phenotypic tests confirmed that Nothofagus isolates efficiently metabolize maltose, while non-Nothofagus strains do not, a pattern linked to recurrent SVs and loss-of-function mutations in MAL33. Consistently, bark-sugar profiling revealed that maltose is abundant in Nothofagus but absent in non-Nothofagus hosts, providing an ecological context for these genomic and phenotypic differences. These results support a model in which northward dispersal of Patagonian lineages into non-Nothofagus forests enriched admixed genotypes, generating genomic mosaics that accumulated structural changes and losses in maltose utilization. This interplay between gene flow and genome flexibility enabled host switching and global expansion, illustrating how ecological transitions reorder genomes and drive microbial diversification.

evolutionary biology↗

bioRxiv2025

High-throughput phenomics of global ant biodiversity

The big data era in biology is underway, but the study of organismal form has been slow to capitalize on advances in imaging and computation. Modern imaging can digitize whole organisms, but low throughput has limited the effort to document morphological diversity. Within the open science initiative Antscan, we applied high-throughput synchrotron X-ray microtomography to capture phenotypes across a diverse and ecologically dominant insect group -- ants. We provide 2193 whole-body 3D ant datasets from 792 species to broadly cover the ant phylogeny with a global scope, also pairing phenomic data with genome sequencing projects. Scans acquired with standardized parameters facilitate automated analysis and free access to data can broaden the audience and incentivize methods development. Antscan presents a scalable approach to create libraries of diverse anatomies, heralding a new era of studies on the evolution, structure, and function of organismal phenotypes.

zoology↗

bioRxiv2025

Allelic variation in MAL33 drives ecological adaptation of maltose metabolism in Saccharomyces eubayanus

Maltose is one of the most abundant sugars in brewers wort, and its efficient utilization is critical for successful fermentation. However, maltose consumption varies naturally among Saccharomyces eubayanus strains isolated from different host trees, such as Quercus and Nothofagus. To identify the genetic determinants underlying these phenotypic differences, we performed bulk segregant analysis (BSA) and quantitative trait loci (QTL) mapping using an F2 offspring derived from QC18 (Quercus-associated) and CL467.1 (Nothofagus-associated) strains. QTL mapping identified two significant genomic regions on subtelomeric loci of chromosomes V-R and XVI-L, each containing complete MAL loci composed of MAL32 (encoding maltase), MAL31 (transporter), and MAL33 (transcriptional activator) genes. Comparative polymorphism analyses identified mutations in MAL32 and MAL33 of QC18, including frameshift mutations resulting in premature stop codons. Functional validation demonstrated that the heterologous expression of MAL33ChrV from CL467.1 fully restored maltose utilization in QC18, indicating the functional presence of MAL33 cis-regulatory sequences and MAL32 and MAL31 genes in QC18. While structural protein predictions identified truncation and impaired functionality in the maltose-responsive activation domain of Mal33p from QC18, overexpression of QC18s own MAL33ChrV allele also improved maltose metabolism, suggesting dosage-dependent transcriptional limitations rather than complete functional loss. These results indicate that allelic variations in the maltose-responsive activation domain of Mal33p lead to differences in maltose consumption between strains. We hypothesized that reduced maltose metabolism in QC18 is an adaptive response to the distinct sugar composition in Quercus robur bark, contrasting with the starch-rich environment of Nothofagus pumilio. These findings highlight subtelomeric MAL gene diversity as a reservoir of evolutionary plasticity, representing a key evolutionary mechanism that influences maltose adaptation among natural Saccharomyces isolates.

evolutionary biology↗

bioRxiv2025

Repeated losses of self-fertility shaped heterozygosity and polyploidy in yeast evolution

Evolutionary transitions in mating strategy have profound consequences for genetic variation and adaptation. In Saccharomyces cerevisiae, mating-type switching is a central feature of the life cycle that enables homothallism, i.e., mating between mitotic descendants of the same haploid cell. Yet heterothallic isolates that have lost this ability are found across diverse niches, indicating that this trait is polymorphic. Here we experimentally characterized loss of mating-type switching in a representative panel of strains. Analysis of 117 telomere- to-telomere genome assemblies revealed multiple independent loss-of-function mutations in the Ho endonuclease gene and structural variants in the silent HML and HMR cassettes, the three loci essential for switching. We estimated that at least 13 independent transitions from homothallism to heterothallism have occurred in the species history. Analysis of the HO genotype of 2,915 strains show that at least 27% are heterothallic. We found that heterothallism is strongly associated with polyploidy and elevated genome-wide heterozygosity, although the strength of these associations varies between populations. Heterothallic isolates are most prevalent in domesticated and clinical clades, consistent with an origin linked to human-associated environments. However, they are also found, though less frequently, in natural niches. Signatures of recombination in HO sequences suggest that outcrossing contributed to the ecological and geographical distribution of the trait. Our findings reveal that mating-type switching has undergone repeated losses in S. cerevisiae evolution, with major consequences for genome architecture and ecological diversification. Significance StatementMating-type switching evolved multiple times in yeasts, enabling haploid selfing, which became a key feature of their life cycles. We show that this trait has been lost repeatedly in the history of Saccharomyces cerevisiae, producing heterothallic isolates that cannot switch mating type. Analysis of thousands of genomes reveals that these losses involve multiple mutations in the Ho endonuclease and structural changes in the silent mating-type cassettes. Heterothallism is associated with polyploidy and increased genome-wide heterozygosity. It is more frequent in domesticated and clinical lineages, but also occurs in natural ecological niches. Our findings illustrate how repeated changes in a single life-history trait can reshape genome architecture and highlight the dynamic interplay between genetics, environment, and evolution in a model eukaryote.

evolutionary biology↗

bioRxiv2025

Converting Spectral Evoked-to-Background Ratio intoTime-Domain Signal-to-Noise Ratio - Validation for HighFrequency Oscillations

N -Interval Fourier Transform Analysis (N -FTA) allows for spectral separation of an evoked target signal from uncorrelated background activity. It computes the frequency-dependent evoked-to-background ratio (EBR). The developed method allows for conversion of the spectral EBR into expected values for improvement of signal-to-noise ratio with progressing sweep count. Our study presents the mathematical basis for this conversion along with a validation for simulated and recorded data. The major findings are: O_LIThree factors enter the calculus of the expected SNR: the ratio of durations of the single sweep cycle and the evoked response window, the mean EBR in the spectral target band, and the sweep count. By conversion of all factors to dB, the expected SNR is defined by their sum. C_LIO_LIThe two fundamental theories governing the improvement of SNR with increasing sweep count, the law of large numbers and the uncertainty principle of signal processing, deliver identical results. C_LIO_LIConversion of EBR to expected SNR was successfully validated by simulated and recorded data and can be applied to all types of evoked data. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/662283v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@6f34d6org.highwire.dtl.DTLVardef@f5d607org.highwire.dtl.DTLVardef@1b6a18eorg.highwire.dtl.DTLVardef@1288e35_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Natural diversity of telomere length distributions across 100 yeast strains

Telomeres gradually shorten at each cell division and telomerase counteracts this shortening by elongating telomere sequences. This dynamic balance between elongation and shortening results in a steady-state telomere length (TL) distribution. We developed a method for detecting telomeric sequences in Saccharomyces cerevisiae genomes from raw Oxford Nanopore Technologies (ONT) sequencing reads, providing a comprehensive view of TL distributions both genome-wide and at individual chromosome extremities. We analyzed the TL distribution in 100 S. cerevisiae strains, representing the genetic and ecological diversity of the species. Our analysis revealed a large diversity in TL distributions within the species, largely driven by inter-extremity differences, ploidy level, and subtelomere structure. Polyploid strains displayed significantly longer telomeres than diploid and haploid strains, and experiments with artificially generated polyploids in two independent genetic backgrounds confirmed that higher ploidy levels lead to telomere elongation. Furthermore, we found that the subtelomeric Y element exerts two distinct and opposing effects: (i) the presence of Y elements at a chromosome extremity is associated with shorter telomeres in cis, but (ii) the overall Y element content in a strain correlates with longer telomeres. Interestingly, the length of the shortest telomeres remained relatively constant across strains, suggesting a selective constraint at the species level. This study reveals the diversity of TL in S. cerevisiae and highlights key factors shaping TL distributions both genome-wide and at individual chromosome extremities.

genomics↗

bioRxiv2025

Identification of Rapaglutin E as An Isoform-specific Inhibitor of Glucose Transporter 1

Natural products rapamycin and FK506 are macrocyclic compounds with therapeutic benefits whose unique scaffold inspired the generation and exploration of the hybrid macrocycle rapafucins. From this library, a potent inhibitor of the facilitative glucose transporter (GLUT), rapaglutin A (RgA) was previously identified. RgA is a pan-GLUT inhibitor of Class I isoforms GLUT1, GLUT3, and GLUT4. Herein, we report the discovery of rapaglutin E (RgE). Unlike RgA, RgE is highly specific for GLUT1. Further characterization revealed that RgE and RgA likely bound to distinct sites on GLUT1 despite their shared FKBP-binding domain, suggesting that the distinct effector domains of RgE and RgA play key roles in recognition of GLUTs. TOC GRAPHIC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/641094v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@d69b12org.highwire.dtl.DTLVardef@15ee120org.highwire.dtl.DTLVardef@e2495org.highwire.dtl.DTLVardef@83e270_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

PRAME expression in melanoma is negatively regulated by TET2-mediated DNA hydroxymethylation

Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5 promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. TeaserMelanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation

cancer biology↗

bioRxiv2024

An integrative taxonomy approach reveals Saccharomyces chiloensis sp. nov. as a newly discovered species from Coastal Patagonia

Species delineation in microorganisms is challenging due to the limited markers available for accurate species assignment. Here, we applied an integrative taxonomy approach, combining extensive sampling, whole-genome sequence-based classification, phenotypic profiling, and assessment of interspecific reproductive isolation. Our work reveals the presence of a distinct Saccharomyces lineage in Nothofagus forests of coastal Patagonia. This lineage, designated Saccharomyces chiloensis sp. nov., exhibits 7% genetic divergence from its sister species S. uvarum, as revealed by whole-genome sequencing and population analyses. The South America-C (SA-C) coastal Patagonia population forms a unique clade closely related to a previously described divergent S. uvarum population from Oceania (AUS, found in Australia and New Zealand). Our species reclassification is supported by a low Ortho Average Nucleotide Identity (OANI) of 93% in SA-C and AUS relative to S. uvarum, which falls below the suggested species delineation threshold of 95%, indicating an independent evolutionary lineage. Hybrid spore viability assessment provided compelling evidence that SA-C and AUS are reproductively isolated from S. uvarum. In addition, we found unique structural variants between S. chiloensis sp. nov. lineages, including large-scale chromosomal translocations and inversions, together with a distinct phenotypic profile, emphasizing their intraspecies genetic distinctiveness. We suggest that S. chiloensis sp. nov diverged from S. uvarum in allopatry due to glaciation, followed by post-glacial dispersal, resulting in distinct lineages on opposite sides of the Pacific Ocean. The discovery of S. chiloensis sp. nov. illustrates the uniqueness of Patagonias coastal biodiversity and underscores the importance of adopting an integrative taxonomic approach in species delineation to unveil cryptic microbial species. The holotype of S. chiloensis sp. nov. is CBS 18620T.

genetics↗

bioRxiv2024

MuPET-Flow: Multiple Ploidy Estimation Tool from Flow cytometry data

SummaryPloidy, representing the number of homologous chromosome sets, can be estimated from flow cytometry data acquired on cells stained with a fluorescent DNA dye. This estimation relies on a combination of tools that often require scripting, individual sample curation, and additional analyses. To automate the ploidy estimation for multiple flow cytometry files, we developed MuPET-Flow--a Shiny graphical user interface tool. MuPET-Flow allows users to visualize cell fluorescence histograms, detect the peaks corresponding to the different cell cycle phases, perform a linear regression using standards, make ploidy or genome size predictions, and export results as figures and table files. The tool was benchmarked with known ploidy datasets, yielding consistent ploidy results. MuPET-Flow produces ploidy results comparable to those from other available tools; however, MuPET-Flow stands out for its user-friendly interface, which allows the whole process to be carried out in one place, considerably speeding up analysis, particularly in projects involving large numbers of samples. Availability and implementation: https://github.com/CintiaG/MuPET-Flow.

bioinformatics↗

bioRxiv2023

A transient but very intense mutational burst occurs during the normal development of yeast colonies

Characterizing the pace of mutation accumulation is crucial for understanding how populations adapt to their environment and for unraveling the intricate dynamics between gradual processes and more sudden burst-like events occurring during cancer development. We engineered the genome of Saccharomyces cerevisiae to measure the rates of single and double mutations, including point mutations, segmental duplications and reciprocal translocations. We found that during the development of wild-type yeast colonies, double mutations occur at rates that are up to 17-fold higher than those expected on the basis of single mutation rates. We found that this excess of double mutations is partially dependent on the ELG1/ATAD5 clamp unloader. Additionally, the double mutants retain wild-type mutation rates, suggesting that they originated from genetically wild-type cells that transiently expressed a mutator phenotype. Numerical simulations based on the experimentally measured mutation rates, confirmed that the excess of double mutations can be accounted for by subpopulations of transient mutators within the colony. These subpopulations would be limited to less than a few thousand cells and temporarily adopt mutation rates multiplied by hundreds or thousands for less than five generations. We found that the majority of double mutations would accumulate sequentially in different cell cycles. The simultaneous acquisition of both mutations during the same cell cycle would be rare and possibly associated with systemic genomic instability. In conclusion, our results suggest that transient hypermutators play a major role in genomic instability and contribute significantly to the mutational load naturally accumulating during the growth of isogenic cell populations. Significance statementUnderstanding the pace at which mutations accumulate is of paramount importance in the field of genome dynamics and evolution. In our study, we unveiled a surprising burst of mutations within growing yeast colonies, occurring independently of external stressors. This discovery indicates that, during short intervals, a small subset of cells within the colonies undergoes a mutational overdrive. Notably, these mutator cells do not represent genetically stable mutators with mutations in genes associated with genome stability. Instead, they stem from a strong mutator phenotype that was transiently expressed in genetically wild-type cells. This phenomenon, previously underestimated or even overlooked, holds significant importance and may have far-reaching implications, particularly in the context of cancer development.

genetics↗

bioRxiv2023

Targeting cancer with small molecule pan-KRAS degraders

Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue (1). However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand (2). Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. One-Sentence SummaryThe most prevalent KRAS variants which drive tumour growth in a major share of cancer patients can be targeted with a single small molecule degrader.

pharmacology and toxicology↗

bioRxiv2023

Domestication signatures in the non-conventional yeast Lachancea cidri

Evaluating domestication signatures beyond model organisms is essential for thoroughly understanding the genotype-phenotype relationship in wild and human-related environments. Structural variations (SVs) can significantly impact phenotypes playing an important role in the physiological adaptation of species to different niches, including during domestication. A detailed characterization of the fitness consequences of these genomic rearrangements, however, is still limited in non-model systems, largely due to the paucity of direct comparisons between domesticated and wild isolates. Here, we used a combination of sequencing strategies to explore major genomic rearrangements in a Lachancea cidri yeast strain isolated from cider (CBS2950) and compared them to those in eight wild isolates from primary forests. Genomic analysis revealed dozens of SVs, including a large reciprocal translocation ([~]16 kb and 500 kb) present in the cider strain, but absent from all wild strains. Interestingly, the number of SVs was higher relative to single-nucleotide polymorphisms in the cider strain, suggesting a significant role on the strains phenotypic variation. The set of SVs identified directly impacts dozens of genes, and likely underpins the greater fermentation performance in the L. cidri CBS2950. Additionally, the large reciprocal translocation affects a proline permease (PUT4) regulatory region, resulting in higher PUT4 transcript levels, which agrees with higher ethanol tolerance, improved cell growth when using proline, and higher amino acid consumption during fermentation. These results suggest that SVs are responsible for the rapid physiological adaptation of yeast to an anthropogenic habitat and demonstrate the key contribution of SVs in adaptive fermentative traits in non-model species. ImportanceThe exploration of domestication signatures associated with anthropogenic niches has predominantly focused on studies conducted on model organisms, such as Saccharomyces cerevisiae, overlooking the potential for comparisons across other non-Saccharomyces species. In our research, employing a combination of long- and short-read data, we found domestication signatures in L. cidri, a non-model species recently isolated from fermentative environments in cider in France. The significance of our study lies in the identification of large array of major genomic rearrangements in a cider strain compared to wild isolates, which underly several fermentative traits. These domestication hallmarks result from structural variants, which are likely responsible for the phenotypic differences between strains, providing a rapid path of adaptation to human-related environments.

genetics↗

bioRxiv2023

Selective inhibitors of the Aurora A-TPX2 protein-protein interaction exhibit in vivo efficacy as targeted anti-mitotic agents

The protein kinase Aurora A, and its close relative, Aurora B, regulate human cell division. Aurora A is frequently overexpressed in cancers of the breast, ovary, pancreas and blood, provoking genome instability and resistance to anti-mitotic chemotherapy. Intracellular localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. Here, we have used fragment-based, structure-guided lead discovery to develop small-molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). These compounds act by novel mechanism compared to existing Aurora A inhibitors and they are highly specific to Aurora A over Aurora B. Our biophysically, structurally and phenotypically validated lead compound, CAM2602, exhibits oral bioavailability, favourable pharmacokinetics, pharmacodynamic biomarker modulation, and arrest of growth in tumour xenografts. Consistent with our original finding that Aurora A overexpression drives taxane-resistance in cancer cells, inhibition of Aurora A-TPX2 PPI synergizes with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.

biochemistry↗