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Andrii Gorelik

@andriigorelik.bsky.social

340 followers 250 following 16 posts

Sir Henry Wellcome Fellow | Oxford with Ivan Ahel & Harvard with Steve Gygi Molecular mechanisms of cysteine modifications | GlcNAc and ADP-ribose Previously: The Francis Crick Institute/Imperial College London (postdoc), University of Dundee (PhD)

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Andrii Gorelik @andriigorelik.bsky.social · Jun 11

New paper! We uncover mechanistic insights into the crosstalk between AHR (aryl hydrocarbon receptor, a transcription factor) and PARP7 (a nuclear enzyme that performs protein ADP-ribosylation). Both are promising cancer drug targets.

Big thanks to all co-authors!

www.pnas.org/doi/10.1073/...

PNAS

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

www.pnas.org

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Reposted by Andrii Gorelik

Cell Chemical Biology @cp-cellchembiol.bsky.social · 1d

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

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.

dlvr.it

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Andrii Gorelik @andriigorelik.bsky.social · 2d

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!

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.

www.nature.com

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Harvard Med Cell Biology @harvardcellbio.bsky.social · 6d

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...

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...

www.biorxiv.org

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Reposted by Andrii Gorelik

Harvard Med Cell Biology @harvardcellbio.bsky.social · 21d

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...

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.

www.nature.com

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ᐯIᑕTOᖇ ᑎIᘔET, ᗰᗪ @nizet.bsky.social · 22d

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

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

YouTube video by neueroadmovies

youtu.be

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ahellab.bsky.social @ahellab.bsky.social · Sep 8

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

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...

rdcu.be

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Lorenz Lab @sonjalorenzlab.bsky.social · Sep 2

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

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...

rdcu.be

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Reposted by Andrii Gorelik

Matthew Freeman @mjafreeman.bsky.social · Sep 1

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...

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?

www.path.ox.ac.uk

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Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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!

Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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.

Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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.

Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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.

Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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

Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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.

Andrii Gorelik @andriigorelik.bsky.social · Aug 28

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...

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…

www.sciencedirect.com

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Ahmad Jomaa @jomaalab.bsky.social · Aug 26

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....

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Chris Parker @chrisgparker.bsky.social · Aug 3

Excited to share a new preprint from the lab. We show that PTMs like phosphorylation & glycosylation dynamically reshape proteome-wide ligandability in cells, including proteins like KRAS. Great collaboration with the Huang Lab, @forlilab.bsky.social and BMS. www.biorxiv.org/content/10.1...

Post-Translational Modifications Remodel Proteome-Wide Ligandability

Post-translational modifications (PTMs) vastly expand the diversity of human proteome, dynamically reshaping protein activity, interactions, and localization in response to environmental, pharmacologi...

www.biorxiv.org

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Ardem Patapoutian @ardemp.bskyverified.social · Jul 18

I still can’t believe that all NIH grants to my colleagues at Harvard and Harvard Medical School have been nullified. And that, as a nation, we’re somehow okay with this illegal, arbitrary, and petty act. Just think of the consequences: scientists, students, and patients will all suffer.

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ahellab.bsky.social @ahellab.bsky.social · Jul 10

A few years back we discovered a dual hybrid protein modification composed of ADP-ribose dinucleotide and ubiquitin (ADPr-Ub). Now we reveal that ADPr-Ub can be further ubiquitinated by the E3 ubiquitin ligase RNF114!
www.nature.com/articles/s41...

www.science.org/doi/10.1126/...

Identification of RNF114 as ADPr-Ub reader through non-hydrolysable ubiquitinated ADP-ribose - Nature Communications

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modificati...

www.nature.com

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Andrii Gorelik @andriigorelik.bsky.social · Jul 10

An amazing paper from van der Heden and Ahel groups! They use clever chemistry to identify RNF114 as a dual ADP-ribose-Ubiquitin reader involved in the DNA damage response! Congratulations to first authors Max, @chatrin-c.bsky.social and Rishov. Happy to have a small contribution in this story

Identification of RNF114 as ADPr-Ub reader through non-hydrolysable ubiquitinated ADP-ribose - Nature Communications

www.nature.com

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Eric Topol @erictopol.bsky.social · Jun 23

This is wild!
Engineering E. coli bacteria to turn plastic waste into paracetamol (Tylenol)
www.nature.com/articles/s41...
www.nature.com/articles/s41...

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ahellab.bsky.social @ahellab.bsky.social · May 24

A few years back we discovered a novel dual hybrid protein modification composed of ADP-ribose dinucleotide and ubiquitin (ADPr-Ub):
pubmed.ncbi.nlm.nih.gov/36197986/

| bioRxiv

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution

www.biorxiv.org

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Andrii Gorelik @andriigorelik.bsky.social · Jun 11

Big thanks to all co-authors at FGC in Cambridge, Hull, Oslo, NCI Frederick and of course @ahellab.bsky.social @dunnschool.bsky.social! I had a lot of fun doing proteomics in Steve Gygi’s lab @harvardcellbio.bsky.social funded by Sir Henry Wellcome Fellowship - thanks to @wellcometrust.bsky.social!

Andrii Gorelik @andriigorelik.bsky.social · Jun 11

Plus, our CRISPR screen identified SOCS3 knockout as a new synthetic lethal interaction with PARP7i. Curiously, SOCS3 is also linked to AHR signalling.

Andrii Gorelik @andriigorelik.bsky.social · Jun 11

Transcriptomics is typically used to study transcription factors, but we took a different approach — examining proteome changes following PARP7 inhibition and AHR activation. This revealed post-translational events that contribute to the synthetic lethality via combined PARP7i and AHR activation.