Lab News

Genome editing creates double-strand breaks (DSBs) that can be repaired through either non-homologous end joining (NHEJ), microhomology-mediated end joining or homology-directed repair (HDR). While NHEJ is quick but error-prone, HDR uses a DNA template for precise edits, allowing targeted changes from single-nucleotide fixes to large gene insertions, greatly benefiting biomedical research and therapies. However, HDR is a relatively inefficient process, and ongoing efforts aim to improve its efficiency, including the use of small molecule inhibitors targeting DNA repair. One such highly potent inhibitor, AZD7648, selectively targets DNA-PKcs, redirecting DNA repair from the error-prone NHEJ pathway to the more precise HDR pathway in both transformed cell lines and primary human cells. However, the potential unintended consequences of its use in genome editing remain largely unexplored.

Are you curious to find out more?

Check out our recent advancement, led by postdoc Grégoire Cullot in a collaboration with the Gehart group (IMHS), Cathomen group (University of Freiburg, Germany) and the Gene Therapy research group of CSL Behring.

This work demonstrated that genome editing with a single Cas9-induced DSB in combination with AZD7648 leads to an increase in HDR, but this was accompanied by Cas9-induced genomic instability at on-target sites, where small-scale NHEJ outcomes were transformed into larger genetic alterations that cannot be detected by short-read sequencing.

Through the use of long-read sequencing, droplet digital PCR (ddPCR) for copy number analysis, single-cell RNA sequencing, and unbiased translocation detection, we discovered that AZD7648 significantly amplifies the frequency of kilobase-scale deletions, chromosome arm loss, and translocations across various cell types.

More broadly, genome editing-induced large-scale genomic alterations might still be largely underestimated. Indeed, these large-scale genomic alterations evade classical genome editing detection assays, typically short-read next-generation sequencing (NGS) and necessitate specific techniques that are not currently commonly used in the genome editing field. This means that clinical genome editing groups might be unaware of potential induced genomic instability and safety risks. Of note, AZD7648 is being tested by many clinical genome editing groups, however our results urge caution when deploying it during genome editing and reinforce the need to investigate genetic outcomes beyond those accessible to short-read target amplicon next-generation sequencing.

For more info check out our new paper in Nature Biotechnology!

X Close

Tijana Nikic received her MSc in Human Biology from LMU Munich, completing her thesis in 2022 with Prof. Dr. Stefan Stricker on understanding astrocyte cell identity and optimizing their reprogramming to neurons. Tijana joined the Corn Lab as a PhD student to investigate the mechanisms of organelle clearance during reticulocyte maturation. Her research interests include functional genomics, unraveling molecular mechanisms driving cellular processes, and advancing genome editing technologies for therapeutic applications.

X Close

We are thrilled to announce that Lilly has successfully defended her PhD! Her research focused on monitoring genome editing by visualizing DNA repair. She developed a high-throughput off-target identification method, enabling tracking of off-targets for thousands of human guide RNAs. A huge congratulations, Dr. van den Venn!

X Close

Young earned his Ph.D. in Biological Sciences from Seoul National University (South Korea) in 2023, where he worked in Dr. V. Narry Kim’s lab, focusing on the molecular and structural insights of siRNA and miRNA production by human Dicer. In November 2024, he joined the Corn Lab as a postdoctoral researcher, with a research focus on leveraging CRISPR technology to address fundamental biological questions.

X Close

Erik Basha received his Bachelor’s degree in Biochemistry and Molecular Biology from the University of Bern in 2023.  Erik joined the Corn Lab in October 2024. He is currently working on his Master’s thesis, focusing on the characterization of unexplored interactions between genes involved in DNA damage repair and other essential cellular mechanisms.

X Close

Our warmest congratulations to Charles on successfully defending his PhD! His commitment and hard work have undoubtedly led to this well-deserved achievement. He developed an innovative, high-sensitivity in situ/in vivo system for monitoring homology search during DNA double-stranded break homology-directed repair (DSBR/HDR). Well done, Dr. Yeh!

X Close

Huge congratulations to Marija on completing her PhD! Her dedication and hard work have paid off! Using a genome-wide CRISPR screen, Marija identified mediators of enucleation in red blood cells. We’re thrilled she’ll continue in the lab as a postdoc- here’s to more amazing accomplishments, Dr. Banovic!

X Close

Jenna Rode received her Bachelor’s degree in Molecular and Cell Biology from UC Berkeley in 2023, working in the lab of Professor Gary Karpen on the role of heterochromatin binding proteins in nuclear organization. Jenna joined the Corn lab in September 2024. She is currently working on her Master’s thesis, focusing on discovering novel mechanisms of DNA-protein crosslink degradation.

X Close

On September 18-19 2024, the Corn Lab hosted an engaging in-person DDREAMM team retreat in Zurich, bringing together researchers for two days of scientific presentations, fruitful discussions, and the exchange of fresh ideas. The event highlighted synergies between the Jackson/Corn lab and fostered brainstorming sessions focused on the latest technologies, scientific advancements, and the evolving landscape of publications in the era of AI and preprints.

Participants also enjoyed valuable networking opportunities, including a scenic hike from Uetliberg to Felsenegg, offering breath-taking views of Zurich and its surroundings.

The retreat was highly effective, sparking new collaborations.

X Close

X Close