Justin Engel

Mechanism of cytarabine-induced neurotoxicity - Nature Certain antimetabolites used to treat cancer are more neurotoxic than others, and it is now shown that this is due to their greater tendency to generate DNA double-stranded breaks, whereas less n...

Cytarabine has been the mainstay for AML treatment for over 50 years. This chemotherapy can lead to problems with movement and balance. Here we explain this neurotoxic side-effect. www.nature.com/articles/s41... Work led by Jia-Cheng Liu, Donpeng Wang and Elsa Callen and terrific collaborators!

The FANCD2-FANCI heterodimer coordinates chromatin openness and cell cycle progression throughout DNA double-strand break repair The FANCD2-FANCI heterodimer contributes to DNA repair at interstrand crosslinks and sites of replication stress. This complex has been physically and mechanistically linked to double-strand break (DSB) repair, but its role in that process remains undefined. Here we show that the FANCD2-FANCI heterodimer dynamically interacts with open chromatin regions, including transient, DSB-induced open chromatin, where it can be stabilized by co-activation by the DNA repair kinase ATM and the Fanconi anemia core ubiquitin ligase. The loaded FANCD2-FANCI heterodimer stabilizes open chromatin and promotes resection and loading of RPA through increased association of BRCA1 and BLM. Chromatin-loaded FANCD2-FANCI has a second distinct function promoting a G2 arrest that is dependent on the ATR-CHK1-WEE1 axis. Our results support a two-step genome surveillance model in which FANCD2-FANCI monitors open chromatin sites and is stably loaded to coordinate DNA repair activities in response to signaling from a DNA repair kinase. ### Competing Interest Statement The authors have declared no competing interest.

Super cool new preprint: FANCD2:FANCI is a sensor of open chromatin, independent of DNA damage, but further increased at double strand breaks.
www.biorxiv.org/content/10.1...

FANCX=FAAP100, new Fanconi Anemia gene
Two new papers identify 3 families with FAAP100 homozygous mutations leading to severe developmental and hematologic abnormalities leading to death in utero or in early life.
www.jci.org/articles/vie...
www.jci.org/articles/vie...

New preprint from the lab led by Yanyang Chen identifies BAF as a key regulator of TREX1 activity at micronuclei.

Postdoctoral Fellow Your group The Cortes-Ciriano group studies the mutational processes and mechanisms of genome instability underpinning tumourigenesis, immune escape, and drug response through the analysis of high-thr...

We have two #postdoc positions open to join my team at @ebi.embl.org in beautiful Cambridge!
We are a mission-driven, highly collaborative and dynamic team located at the Wellcome Genome Campus, one of the most exciting hubs in the world focused on biomedical research 👇

Excited to share our new pre-print. Direct, ensemble FRET assays developed by our lab reveal that assembly of Rad51 filaments at stalled replication sites via RPA/Rad51 exchange causes complete & irreversible PCNA unloading. Big implications for interplay between human DNA damage tolerance pathways

“You don’t take these jobs that pay worse and have insane hours and are really stressful unless you care about helping others and taking our love for science and translating that into something that can improve people’s lives.”

The transcriptomic architecture of common cancers reflects synthetic lethal interactions - Nature Genetics Tumor cells upregulate compensatory buffering genes following tumor suppressor loss. These genes may represent new synthetic lethal partners that could be harnessed therapeutically.

We show transcriptomic buffering of tumour suppressor loss via syn. lethal genes is not anecdotal but a cancer hallmark. Buffering also seen in BRCAness, predicts penetrant syn leth effects and outcome. @icr.ac.uk @cancerresearchuk.org @breastcancernow.bsky.social www.nature.com/articles/s41...

Please check out our preprint where we find that mitotic transcription helps ensure ecDNA inheritance through chromosomal tethering:

www.biorxiv.org/content/10.1...

A research lab from Northwestern, chosen because it's generic and sort of zoomed out. Three scientists are visible in lab coats, and there are benches and shelving, with glass along one wall showing another high-rise building nearby. Overhead fluorescents provide light.

This is a room where we turn very modest salaries and budgets (and lots of coffee) into new knowledge, life-saving innovations, and technology that feeds business growth.

It's literally the loom that spins hay into gold but these numpties are suddenly worried about the cost of hay.

This one looks exactly like two recently divided daughter cells with an interphase bridge!

“What is seven days?” Is the apparent Jeopardy answer to the question of how long it would take to dismantle what made America great and its standing in the world.

Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability Nature Cancer - Whalen et al. report that increased DNA end resection in BRCA-deficient, PARP inhibitor-resistant cancers leads to increased sensitivity to DNA nicks, limiting tumor formation in...

Congratulations to Jenna Whalen on her Nature Cancer paper out today-a distinct take on nicks and their toxicity! rdcu.be/d60Td

The PST repeat region of MDC1 is a tunable multivalent chromatin tethering domain DNA double strand breaks (DSBs) are widely considered the most cytotoxic DNA lesions occurring in cells because they physically disrupt the connectivity of the DNA double helix. Homologous recombinati...

Super excited to share our most recent pre-print, lead by K99 fellow @heyzajr.bsky.social, who will be starting his own lab at Wayne State University in February!

The question is how are DNA breaks held together during HR?? 1/n

www.biorxiv.org/content/10.1...

Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint - Nature Cell Biology Hervé, Scelfo et al. show that chromosome mis-segregation induces mTORC2- and ATR-mediated p53 activation through a mechanosensitive checkpoint at the nuclear envelope triggered by altered heterochrom...

#1 Happy to share our last work published in @NatureCellBio about a new cell cycle checkpoint that senses nuclear shape & mechanics to guarantee genome integrity
www.nature.com/articles/s41.... Great work from @sol-herve.bsky.social & Andrea Scelfo in close collaboration with @katemiro.bsky.social

Happy holidays from the Ly Lab! Wishing all of your papers and proposals are met with fair and favorable reviews in 2025!

Engineered extrachromosomal oncogene amplifications promote tumorigenesis - Nature Large extrachromosomal DNAs are engineered using a CRISPR- and Cre–loxP-based approach and shown to drive cancer in mouse models, with potential applications in determining the role of oncogene a...

🧪1/ 🚨New paper on ecDNAs from our lab!
We reveal a strategy to engineer extrachromosomal DNA (ecDNA) amplifications in cells & mice. Let's dive in! Let’s dive in! 🧵👇
www.nature.com/articles/s41...

DNA Break Repair by Homologous Recombination (2024) Drew Berry wehi.tv YouTube video by WEHImovies

Delighted to publish my new molecular animation:

DNA Break Repair by Homologous Recombination

youtu.be/Xe-83tBcxhs

Synthetic lethal strategies for the development of cancer therapeutics - Nature Reviews Clinical Oncology The experience with PARP inhibitors provides evidence of the clinical utility of synthetic lethality, whereby the simultaneous presence of two specific alterations is required for antitumour activity....

Review on synthetic lethal strategies in oncology, with a small contribution from yours truly.

www.nature.com/articles/s41...

Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability Nature Communications - DNA repeats can lengthen or shorten during their replication, which may lead to a human disease. Here, the authors discovered that an essential replication protein, Mcm10,...

Mcm10 — an important replication and elongation factor, counteracts repeat instability and ensures survival of yeast cells containing large homopurine homopyrimidine repeats, such as GAA associated with Friedreich’s Ataxia and AAGGG associated with CANVAS. 🧬 @natureportfolio.bsky.social

Congrats!!

TTF2 promotes replisome eviction from stalled forks in mitosis https://www.biorxiv.org/content/10.1101/2024.11.30.626186v1 When cells enter mitosis with under-replicated DNA, sister chromosome segregation is compromised, wh

TTF2 promotes replisome eviction from stalled forks in mitosis https://www.biorxiv.org/content/10.1101/2024.11.30.626186v1

From @seedgeorge.bsky.social Johann De Bono and colleagues (us !). In BRCA2m CRPC, reversion mutations emerge in 79% by end of olaparib treatment. Reversions associate with PFS and OS. Rare subclones without BRCA2-loss also emerge authors.elsevier.com/sd/article/S...

Thank you @gabriellebrewer.bsky.social for highlighting our work in Nature Reviews Cancer, led by grad student @justeng95.bsky.social.

Check out the original paper in Cell here:
www.cell.com/cell/fulltex...

Here's a summary thread from "the other site": x.com/PeterLyLab/s...

Normal breast tissues harbour rare populations of aneuploid epithelial cells - Nature Using single-cell DNA sequencing we show that most healthy women harbour rare populations of aneuploid epithelial cells with copy number alteration events in their breast tissue that expand and accumu...

new out in Nature www.nature.com/articles/s41...

USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity USP1 targeting improves PARP inhibitors effectiveness in ovarian cancer by regulating PARP1 trapping and catalytic activity.

Happy to share on Bluesky as my first post our new study on #chemoresistance in #ovarian-cancer just published in #Science_Advances. We show that #USP1 binds and regulates the activity of #PARP1 and that their combined inhibition sinergistically kills cancer cells.👇
www.science.org/doi/10.1126/...