Jacob Corn
California
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Articles by Jacob Corn
Chemogenomic maps reveal a PRDX1-dependent iron–damage axis in the DNA damage response
Abstract The DNA damage response (DDR) is a sophisticated network of cellular pathways whose perturbation leads to genome instability and is a key hallmark of oncogenesis. Here, we present data from 32 genome-scale loss-of-function CRISPR interference chemical–genetic screens with inhibitors targeting core constituents of the DDR machinery (PARP, ATR, ATM, DNAPK and WEE1), as both single agents and in combination with poly(ADP-ribose) polymerase inhibitors.
The use of homology-directed repair in a complex landscape of genome editors
Genome editing is maturing from a one-size-fits-all system into a highly specialized ecosystem that includes a dizzying array of tools. In this Comment, we discuss the current and future use of Cas-induced homology-directed repair for precise genetic modification, as it complements an ever-expanding genome editing toolbox.
CRISPR in clinical oncology: translational advances from molecular diagnostics to therapeutics
Abstract Cancer care is increasingly driven by molecular classification, yet many key oncogenic drivers remain undruggable, and intrinsic or acquired resistance to treatment frequently limits durable clinical benefit. CRISPR–Cas technologies provide a modular, programmable platform to interrogate and directly manipulate cancer biology via sequence-specific targeting of DNA or RNA and have advanced from experimental tools to the early stages of clinical translation.
An SP110–SP100 axis is a critical regulator of promyelocytic leukaemia body dynamics and mitotic fidelity
Abstract Stimulation of the innate immune system by foreign RNA elicits a potent interferon response and can trigger cell death. The mechanisms by which cells balance a robust response with cell-intrinsic lethality are still being uncovered. Here, using genome-wide CRISPR–Cas9 genetic screens with triphosphorylated RNA stimulation, we discover that promyelocytic leukaemia (PML) nuclear body-localized speckled protein 110 (SP110) is a potent inhibitor of type 1 interferon-driven cell death.
ERCC6L2 ensures repair fidelity for staggered-end DNA double-strand breaks - Nature Communications
Abstract DNA double-strand breaks (DSBs) both pose threats to genome integrity and are commonly used for genome editing applications. Structural features of DSB ends play key roles in determining DNA repair pathway usage and outcomes during genome editing, but the cellular factors involved in these processes are only partially known.
FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry
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Keywords gene regulation enhancers transcription factors T cells CRISPR FOXP3 epigenetics regulatory T cells Introduction Lineage-defining factors are tightly regulated by cis-regulatory elements (CREs) to ensure proper cell-type-specific expression.1,2,3 Genes encoding these factors are often marked with extended regions of chromatin modifications associated with CRE activity.3,4 These “super enhancers” harbor distinct CREs occupied by distinct sets of transcription factors (TFs) and...
By Jennifer M Umhoefer, Maya M. Arce, Sivakanthan Kasinathan, Sean Whalen, Rama Dajani, Sanjana Subramanya, Laine E. Goudy, Julia A. Belk, Royce Zhou, Minh Pham, Wenxi Zhang, Rosmely Hernandez, Carinna Tran, Nikhita Kirthivasan, Jacob W. Freimer, Cody T. Mowery, Vinh Nguyen, Mineto Ota, Benjamin G. Gowen, Dimitre R. Simeonov, Zhongmei Li, Andy Chen, Jacob Corn, Howard Chang, Qizhi Tang, Luke A Gilbert, Ansuman T. Satpathy, Katherine S. Pollard, Alexander Marson, Gemma L. Curie
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Cell Press
Verified
WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2 - Nature Communications
Abstract Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between WEE1 small-molecule inhibitors and defects in mRNA translation, mediated by activation of the integrated stress response (ISR) through the kinase GCN2. Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775.
Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes - Nature Biotechnology
Abstract Base editors create precise genomic edits by directing nucleobase deamination or removal without inducing double-stranded DNA breaks. However, a vast chemical space of other DNA modifications remains to be explored for genome editing. Here we harness the bacterial antiphage toxin DarT2 to append ADP-ribosyl moieties to DNA, unlocking distinct editing outcomes in bacteria versus eukaryotes.
A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles
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Keywords innate immunity E3 ubiquitin ligase helicase ZNFX1 nucleic acid sensor non-canonical ubiquitination Introduction Innate immunity targets microbial invaders via pathogen-associated molecular patterns (PAMPs).1 Viruses are typically recognized by the presence of nucleic acids (NAs) in incorrect cellular compartments.
By Daniel B. Grabarczyk, Eric Aird, Paul C. Kirchgatterer, Julian F. Ehrmann, Robert Kurzbauer, Lillie Bell, Max J. Kellner, Ritika Aggarwal, Alexander Schleiffer, Anton Meinhart, Gijs A. Versteeg, Josef M Penninger, Lukas S. Stelzl, Moritz M. Gaidt, Ingrid Tessmer, Jacob Corn, Tim Clausen, Vanessa Reznikow, Victoria Faas, Luiza Deszcz
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Cell Press
Verified
Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells - Nature Genetics
Abstract Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity.
Recursive Editing improves homology-directed repair through retargeting of undesired outcomes - Nature Communications
Abstract CRISPR-Cas induced homology-directed repair (HDR) enables the installation of a broad range of precise genomic modifications from an exogenous donor template. However, applications of HDR in human cells are often hampered by poor efficiency, stemming from a preference for error-prone end joining pathways that yield short insertions and deletions.
Genome editing at the crossroads of scandal and cure
CRISPR-Cas technology allows the genome of cells to be altered relatively easily. This also brings the therapy of hereditary diseases within reach. Credit: Colourbox Genetic modification of babies in China one year ago was universally condemned. At the same time, CRISPR treatments are on their way into our clinics. Jacob Corn explains the difference.
Advances in genome editing through control of DNA repair pathways
Abstract Eukaryotic cells deploy overlapping repair pathways to resolve DNA damage. Advancements in genome editing take advantage of these pathways to produce permanent genetic changes. Despite recent improvements, genome editing can produce diverse outcomes that can introduce risks in clinical applications. Although homology-directed repair is attractive for its ability to encode precise edits, it is particularly difficult in human cells.
Sometimes you’re the scooper, and sometimes you get scooped: How to turn both into something good
We are Jacob Corn and Jin-Soo Kim, two researchers working in the fast-moving field of genome editing. What follows are our personal thoughts on experiencing PLOS’s new complementary research policy firsthand. It’s a nightmare most scientists have experienced at least once.
Enhanced Genome Editing with Cas9 Ribonucleoprotein in Diverse Cells and Organisms
These experiments show how pre-assembled Cas9 RNP can be used to manipulate the genomes of primary cells and whole organisms. Researchers purify or purchase Cas9 protein and sgRNA, combine the two components to pre-form the complex, and introduce the RNP into their cells or organism of interest. After allowing enough time for editing to occur and for offspring of the next generation to be born (if applicable), check for phenotypes and/or collect cells for genotyping.
Another View: CRISPR will change lives, but not only through genetic engineering
The whole world is abuzz about CRISPR, the new technology that’s allowing scientists to easily edit genetic data. This development is poised to fundamentally change our relationship with genetic disease. In the future, we may be able to do more than treat the symptoms of genetic disease - instead, we might strike directly at the DNA causing maladies such as “bubble boy” syndrome, muscular dystrophy and sickle cell disease.
Another View: CRISPR will change lives, but not only through genetic engineering
The whole world is abuzz about CRISPR, the new technology that’s allowing scientists to easily edit genetic data. This development is poised to fundamentally change our relationship with genetic disease. In the future, we may be able to do more than treat the symptoms of genetic disease - instead, we might strike directly at the DNA causing maladies such as “bubble boy” syndrome, muscular dystrophy and sickle cell disease.
CRISPR will change lives, but not only through genetic engineering
Each week, In Theory takes on a big idea in the news and explores it from a range of perspectives. This week we’re talking about human genetic engineering. Jacob Corn is scientific director of the Innovative Genomics Institute and a faculty member at the University of California at Berkeley. His research focuses on bringing about the end of genetic disease through the development and application of next-generation genome editing technologies.
Translating the statement on human germline editing
Scientists, bioethicists, policy makers, and more met Dec 1-3 at the national academies for the International Summit on Human Gene Editing. The topics were well chosen, the speakers were eloquent, and the summit ended with a responsible and forward thinking statement about the future of gene editing. But what does it mean? The summit statement is very clear to a scientist, but in some places is opaque as mud to the lay person.
The explosion of CRISPR/Cas9
It seems like every time you turn around, there’s another paper that mentions CRISPR/Cas9. Just how fast has the field exploded?
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