Andrii Gorelik

The PARP Family & ADP-ribosylation Cold Spring Harbor Laboratory Meetings & Courses -- a private, non-profit institution with research programs in cancer, neuroscience, plant biology, genomics, bioinformatics.

Just two more days to submit abstracts for the "PARP Family and ADP-ribosylation CSHL meeting. We have an amazing lineup of speakers. The majority of speakers are selected from abstracts. Don't miss out! meetings.cshl.edu/meetings.asp...

New year, new preprint! 🎊

We are excited to share our recent work on #E3 ligase regulation in #metabolism!

www.biorxiv.org/content/10.6...

#ubiquitin #targetedproteindegradation #chemicalbiology

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PARG regulates the proteasomal degradation of TARG1 ADP-ribosylation (ADPr) is a reversible modification of macromolecules critical for the regulation of genome stability, stress responses, and proteost…

Learn more about the interplay between ADP-ribosylation and ubiquitination: PARG regulates proteasomal degradation of the ADP-ribosyl hydrolase TARG1 by preventing PAR-dependent ubiquitination mediated by the E3 ligases HUWE1 and TRIP12
www.sciencedirect.com/science/arti...

Ubiquitin pathway blockade reveals endogenous ADP-ribosylation marking PARP7 and AHR for degradation - The EMBO Journal ADP-ribosylation is an important protein post-translational modification catalysed by a family of PARP enzymes in humans and is involved in DNA damage and immunity among other processes. While poly-AD...

Check out our latest story on AHR and PARP7 (TIPARP) degradation by the ADP-ribose-targeting E3 ligase DTX2 in the first issue of 2026 @embojournal.org!
link.springer.com/article/10.1...

Membrane editing with proximity labeling reveals regulators of lipid homeostasis - Nature Chemical Biology Coupling an optogenetic lipid-modifying enzyme with proximity labeling reveals protein networks and mechanisms regulating lipid homeostasis in the membranes of target organelles.

Thrilled to share our latest study, led by @reikatei.bsky.social, in @natchembio.nature.com! We began by asking a simple question—how do cells know if they have too much of a lipid in a particular membrane, and how do they respond to rectify this imbalance?
www.nature.com/articles/s41...
More info 👇

Ninhydrin as a covalent warhead for chemical proteomic-enabled discovery and selective engagement of reactive arginines Covalent molecules have emerged as next-generation therapeutics and as powerful tools for perturbing fundamental biological processes. Chemical proteomic methods to screen for reactive proteinaceous a...

Is arginine the new cysteine?! Check out our lab's latest in collaboration with @ianseiple.bsky.social's team where we introduce ninhydrin as a selective covalent warhead and probe targeting reactive arginines.
www.biorxiv.org/content/10.6...

An interactive resource mapping the proteome and reactive cysteine landscape across the NCI-60 reveals cell and tissue-specific profiles Montaño et al. generate an integrated proteomic and cysteine reactivity resource for the NCI-60 cancer cell line panel, offering quantitative data on over 12,000 proteins and 36,000 cysteines to enable future studies on protein function, cysteine biology, and covalent drug discovery.

Online now! Online now! An interactive resource mapping the proteome and reactive cysteine landscape across the NCI-60 reveals cell and tissue-specific profiles #chembiol

Proteomics analysis of flow cytometry-based isolated pathogen-containing phagosomes at The University of Manchester on FindAPhD.com PhD Project - Proteomics analysis of flow cytometry-based isolated pathogen-containing phagosomes at The University of Manchester, listed on FindAPhD.com

I have a PhD position available with start date September 2026 at the University of Manchester.

Proteomics analysis of flow cytometry-based isolated pathogen-containing phagosomes

Due to funding requirements, this position is for UK home students only.

www.findaphd.com/phds/project...

SAVE THE DATE!
The EMBO workshop "Ubiquitin and Ubiquitin-like proteins in Health and Disease" will be on September 2026.
Exciting line up of talks and an amazing location!
Organised by @kulathu.bsky.social, @merbllab.bsky.social, @simonapolo.bsky.social, Claudio Joazeiro.
Registration open soon.

Filament formation and NAD processing by noncanonical human FAM118 sirtuins Nature Structural & Molecular Biology - Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that...

Very happy to share our collaborative project on FAM118 proteins - noncanonical sirtuins that form filaments and process NAD in human and other vertebrate cells.

This mechanism fits nicely with our previous report showing that AHR activation increases sensitivity to PARP7 inhibition in lung cancer cells. When PARP7 is inhibited (no ADP-ribosylation = no DTX2 interaction), AHR is stabilised in the nucleus and drives excessive transcription of its targets

Mono-ADP-ribosylation as a degradation mark?
@andriigorelik.bsky.social, Ivan Ahel et al observe increased ADP-ribosylation of aryl hydrocarbon receptor (AHR) & PARP7 upon ubiquitin-proteasome blockage, crosstalk with DTX2 E3, as rapid AHR-transcription off-switch
www.embopress.org/doi/full/10....

Ubiquitin pathway blockade reveals endogenous ADP-ribosylation marking PARP7 and AHR for degradation | The EMBO Journal imageimageDegradation mechanisms of transcriptionally active aryl hydrocarbon receptor (AHR) are unclear. This work reveals that PARP7 ADP-ribosylates itself and ligand-bound AHR, creating a recogniti...

In our latest study we show that ligand-activated transcription factor AHR (environmental sensor) is ADP-ribosylated by PARP7. This ADP-ribose mark is recognised by the E3 ubiquitin ligase DTX2 targeting AHR for proteasomal degradation, enabling cells to rapidly shut down AHR-mediated transcription.

Amazing work! Congratulations!

CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity Li et al. identify XZA-1 as a small-molecule activator of HADH that increases acetoacetyl-CoA, inducing CBX4 K106 acetoacetylation. This modification suppresses CBX4 SUMO E3 ligase activity, reduces HIF-1α SUMOylation, and attenuates its transcriptional activity.

Online now! CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity #chembiol

Multi-domain O-GlcNAcase structures reveal allosteric regulatory mechanisms - Nature Communications This work reveals how a regulatory domain in O-GlcNAc hydrolase (OGA) shapes enzyme flexibility and activity, uncovering mechanisms that help maintain O-GlcNAc balance in cells.

Out in @natcomms.nature.com: Cryo-EM structure of the pseudo-HAT-containing O-GlcNAcase!

Especially exciting since multiple companies are developing O-GlcNAcase inhibitors for Alzheimer's disease (tau is O-GlcNAcylated). Glad to have a small contribution in this story.
Congrats to all authors!

Giant DNA viruses encode a hallmark translation initiation complex of eukaryotic life In contrast to living organisms, viruses were long thought to lack protein synthesis machinery and instead depend on host factors to translate viral transcripts. Here, we discover that giant DNA virus...

Historically, viruses were thought to primarily use host cell's translational machinery. New work from @harvardcellbio.bsky.social faculty Amy Lee reveals that a giant DNA virus encodes its own IF4F initiation complex, suggesting an unexpected evolutionary innovation. www.biorxiv.org/content/10.1...

Covariation MS uncovers a protein that controls cysteine catabolism - Nature A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

New work from our own Chouchani Lab finds that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine in response to altered Cysteine levels. www.nature.com/articles/s41...

CATHEDRALS OF CULTURE - Clip ROBERT REDFORD: Salk Institute -- La Jolla, California, USA - HD YouTube video by neueroadmovies

Robert Redford (RIP) survived a childhood bout of polio though bedridden for 2 weeks

In 2014, he directed a short film on the architecture and mission of La Jolla's Salk Institute—honoring founder Jonas Salk, inventor of the polio vaccine that has saved countless lives, and architect Louis Kahn

The rise of ADP-ribose–ubiquitin Nature Structural & Molecular Biology - Post-translational modifications show mechanistic crosstalk, exemplified by the ADP-ribose–ubiquitin hybrid signal, in which one post-translational...

A few years back we discovered a dual hybrid protein modification composed of an ADP-ribose dinucleotide and the ubiquitin moieties (ADPr-Ub). Here you can read our review that will give you an update on this increasingly popular topic:
rdcu.be/eETIT

Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1 Nature Communications - Ubiquitination is a versatile modification system in eukaryotic cells. Here, the authors unveil that the ubiquitin ligase HUWE1 can modify drug-like small-molecule...

Delighted to share our work on cellular ubiquitination of drug-like compounds by HUWE1 - a surprising journey! Kudos to all contributors & first authors, Barbara Orth and Pavel Pohl. Sincere thanks to @ireserra.bsky.social ‬ #NatCommun for expertly guiding the winding publishing path.
rdcu.be/eDzPk

Group Leader Career Development Fellowships - Dunn School Are you an early career researcher interested in the cell or molecular mechanisms underlying disease? Do you have an outstanding record and an innovative research plan?

Are you a postdoc interested in the mechanisms of disease?

Do you have a great record and an exciting vision?

Come and start your own lab @dunnschool.bsky.social by applying for sponsorship for early career fellowships.

Deadline 30th September...pass it on!

www.path.ox.ac.uk/work-with-us...

Congratulations to first authors Gregor Lueg, James Zhang, Monica Faronato and big thanks to all co-authors for being amazing colleagues and collaborators!

Special thanks to Ed Tate and Dinis Calado for supervising this exciting project!

Finally, we show that an orally bioavailable NMTi eliminates MYC-deregulated tumours in vivo without overt toxicity. MYC oncogene is deregulated in >50% of cancers but is notoriously difficult to target. Our discovery of the MYC-NMTi synthetic lethality circumvents this obstacle.

Fortuitously, we discover that a patient mutation in NDUFAF4, associated with a neurological disorder called the Leigh syndrome, also leads to loss of myristoylation on NDUFAF4, its degradation and therefore dysfunctional respiratory complex I.

Mechanistically, NMTi-induced mitochondrial failure is concurrent with loss of myristoylation on respiratory complex I assembly factor NDUFAF4 with its subsequent proteasomal degradation via the glycine N-degron mechanism.

Using proteomics, we discovered that NMTi cause mitochondrial dysfunction (complex I defects) in high-MYC cancer cells.

We screened hundreds of cancer cell lines using a potent and selective N-myristoyltransferase inhibitor (NMTi) and found a strong correlation between increased NMTi sensitivity and MYC deregulation with death of high (vs low) MYC cancer cells.

MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic ra…

Happy to share that my first-author paper from my postdoc at Imperial @imperialcollegeldn.bsky.social and The Francis Crick Institute @crick.ac.uk is now published in Cell Reports!

www.sciencedirect.com/science/arti...

Want to know how lipidation of some nascent chains takes place by NMT2-- Check our latest work on how NAC couples Protein Synthesis with Nascent Polypeptide Myristoylation on the Ribosome out today @embojournal.org‬: www.embopress.org/doi/full/10....