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Articles by David E. Root
Author Correction: DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells
Correction to: Nature https://doi.org/10.1038/s41586-018-0670-5 Published online 31 October 2018 In the version of the article initially published, in Extended Data Fig. 2c (lower panel), an error occurred during figure assembly, resulting in the incorrect blot being included for the tubulin loading control. The panel has now been replaced with the correct image from the original contemporaneous experiment and is shown below as Fig. 1.
Aurora kinase A is a synthetic lethal target in FANCA-deficient cancers
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Abstract Loss-of-function genomic alterations in FANCA occur across multiple cancer types, yet no molecularly tailored therapies have successfully exploited this potential vulnerability. Using complementary unbiased approaches, including a genome-wide CRISPR/Cas9 loss-of-function screen and a high-throughput drug screen in isogenic cancer cell-based models, we identified Aurora kinase A (AURKA) as a reproducible synthetic lethal target of FANCA-deficient cancers.
By Dilara Akhoundova, Martín González-Fernández, Aavash Baral, Andrej Benjak, Carmen Perry, Saskia Hussung, Sina Maletti, Aino Paasinen-Sohns, Marika Lehner, Bastian Dislich, Erik Vassella, Simone de Brot, Carmen Cardozo, Ralph Fritsch, Clelia Pistoni, Seynabou Diop, Phillip Thienger, Muriel Jaquet, Smruthy Sivakumar, David E. Root, Paola Francica, Sven Rottenberg, Mark A. Rubin, Ladina Hörtensteiner, Lea Lingg, Therese Waldburger, Petros Tsiridis, Taina Kaiponen, Mariana Ricca, Christopher McDermott-Roe
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Nature
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Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis - Nature Communications
Abstract Cuproptosis is a recently described form of regulated cell death triggered by ionophore-induced copper (Cu) overload in mitochondria. It is critically dependent on ferredoxin 1 (FDX1), a mitochondrial iron-sulfur cluster containing protein that acts as an electron shuttle. FDX1 reduces ionophore-bound Cu(II) to Cu(I), thereby triggering its release, and promotes mitochondrial protein lipoylation, which is directly targeted by the released copper to drive cell death.
Morphological map of under- and overexpression of genes in human cells - Nature Methods
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Abstract Cell Painting images offer valuable insights into a cell’s state and enable many biological applications, but publicly available arrayed datasets only include hundreds of genes perturbed. The JUMP Cell Painting Consortium perturbed roughly 75% of the protein-coding genome in human U-2 OS cells, generating a rich resource of single-cell images and extracted features.
By William Charles, Beth Cimini, John G. Doench, Jessica D. Ewald, Marzieh Haghighi, Yu Han, Alexandr A. Kalinin, Nicola McCarthy Verified, Nikita Moshkov, David E. Root, Peter Sommer, Rahul Veettil, Sui Wang, Erin Weisbart, Andrei Zinovyev, Shantanu Singh, Colin J. Fuller, Francesco Rubbo, Douglas W. Selinger
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Nature
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Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries - Nature Communications
Abstract Reducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale.
Author Correction: Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants - Nature Communications
Correction to: Nature Communications https://doi.org/10.1038/s41467-024-45594-4, published online 28 March 2024 The original version of this Article contained an error in Fig. 4b, in which the symbols for LacZ and EGFR WT were switched. This has been corrected in both the PDF and HTML versions of the Article.
Three million images and morphological profiles of cells treated with matched chemical and genetic perturbations - Nature Methods
Abstract The identification of genetic and chemical perturbations with similar impacts on cell morphology can elucidate compounds’ mechanisms of action or novel regulators of genetic pathways. Research on methods for identifying such similarities has lagged due to a lack of carefully designed and well-annotated image sets of cells treated with chemical and genetic perturbations.
Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin - Communications Biology
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Abstract Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models.
By Benjamin Lee, Yongdong Su, Jenny Shim, Diego Almanza, Xiaoping Yang, Glenn S. Cowley, Brittaney A. Leeper, Manali Rupji, Manoj Bhasin, Brian D. Crompton, Keith L. Ligon, David E. Root, Andrew Murphy, David Weinstock, Prafulla C. Gokhale, Miguel Rivera, Elizabeth Mullen, Kimberly Stegmaier, Kelly Goldsmith, William Hahn
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Nature
Verified
Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants - Nature Communications
Abstract The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function.
Mapping the landscape of genetic dependencies in chordoma - Nature Communications
Abstract Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets.
In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer - Nature Immunology
Abstract The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1b/HLA-E.
Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex - Nature
Abstract Receptor tyrosine kinase (RTK)–RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2–MRAS–PP1C holophosphatase complex functions as a key regulator of RTK–RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1.
Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state - Nature Communications
Abstract PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity.
Phosphate dysregulation via the XPR1–KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer - Nature Cancer
Abstract Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR–Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2—encoding a phosphate importer—is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo.
Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects - Genome Biology
Genome Biology volume 22, Article number: 343 (2021) Cite this article Abstract CRISPR loss of function screens are powerful tools to interrogate biology but exhibit a number of biases and artifacts that can confound the results. Here, we introduce Chronos, an algorithm for inferring gene knockout fitness effects based on an explicit model of cell proliferation dynamics after CRISPR gene knockout. We test Chronos on two pan-cancer CRISPR datasets and one longitudinal CRISPR screen.
Noncanonical open reading frames encode functional proteins essential for cancer cell survival
Abstract Although genomic analyses predict many noncanonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins. Here we experimentally interrogated 553 candidates selected from noncanonical ORF datasets. Of these, 57 induced viability defects when knocked out in human cancer cell lines. Following ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes.
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