Grant Stewart

What specific targets & roles are there for all distinct polyubiquitin chain types?
Niels Mailand, Robert Shearer et al profile a panel of #ubiquitin replacement cell lines, implicating K29 chains in chromatin regulation via SUV39H1 destabilization
www.embopress.org/doi/full/10....

See our paper “Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1”. Using biochemistry, we show how DNA incisions by the MutLγ nuclease can lead to expansions, and how expansion is prevented by FAN1. Well done Issam and Valentina!

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

A nuclease-driven mechanism of post-replicative ssDNA gap suppression. The persistence of post-replicative ssDNA gaps following PRIMPOL-mediated replication repriming is linked to chemosensitivity, and in all models reported to date the nuclease MRE11 has been implicated...

New preprint from the lab for any DNA repair or replication stress geeks out there!

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

DDIAS is a single-stranded DNA-binding effector of the TOPBP1-CIP2A complex in mitosis DNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segre...

Delighted to share our lab's first preprint identifying DDIAS as a mitotic DNA repair protein. Great collaboration with the @andrewblackford.bsky.social, @tcr-miller.bsky.social and @profstewartlab.bsky.social labs, and many more. Read the paper here: www.biorxiv.org/content/10.1...

Great work by the Kitagawa lab about DONSON regulating centrosome duplication is finally out in Nature Comms

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

The RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling - Nature Communications DNA replication stress is a driver of genome instability. Here, the authors identify a role of the E3 ligase RNF25 in promoting replication stress tolerance. Mechanistically, RNF25 recruits the fork p...

Great paper by the Vaziri lab about the role of RNF25 regulating the DDR independently of its E3 ligase activity!

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

USP1/UAF1 targets polyubiquitinated PCNA with an exo-cleavage mechanism that can temporarily enrich for monoubiquitinated PCNA - Nature Communications DNA damage tolerance is regulated by ubiquitination of PCNA. Here, the authors present kinetic and structural studies showing that USP1/UAF1 prefers trimming K63- and K48-ubiquitin chains down over cl...

I'm very proud that our paper, and with that the main project of my PhD, has just been published by @natcomms.nature.com! 🎉
Here, we reveal the unique, molecular mechanism by which USP1/UAF1 cleaves ubiquitin chains on PCNA, which may direct DNA damage tolerance.

doi.org/10.1038/s414...

Well deserved!

Well done Ivan. Beautiful work!

The DNA replication checkpoint limits Okazaki fragment accumulation to protect and restart stalled forks Canal et al. used biochemical reconstitution of DNA replication to show that continued Okazaki fragment synthesis after nucleotide exhaustion depletes PCNA, RFC, and DNA polymerases ε and δ, deprotecting replication forks and impairing restart. By limiting Okazaki fragment generation and factor depletion, the replication checkpoint protects forks, allows restart, and promotes survival.

Online Now: The DNA replication checkpoint limits Okazaki fragment accumulation to protect and restart stalled forks Online now:

Birmingham Centre for Genome Biology 2025 Anniversary Conference, 11-12 September! This symposium covers DDR and gene regulation. Register here:
uobevents.eventsair.com/birmingham-c...

Postdoctoral Research Associate in the Blackford Group A position as Postdoctoral Research Associate is available at the Department of Cellular and Molecular Medicine, in the group headed by Dr. Andrew Blackford. Th

We’re #hiring, please share! A fully funded #postdoc position is available in my lab to work on DNA damage response mechanisms.

Please get in touch with your CV if you are interested; closing date: 27th June 2025.

More details here: candidate.hr-manager.net/ApplicationI...

USP37 prevents premature disassembly of stressed replisomes by TRAIP - Nature Communications The replicative helicase CMG is targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP. This study describes how the de-ubiquitylating enzyme USP37 protects genome stability by preventin...

Awesome paper from the Steve Jackson and Johannes Walter labs about USP37 and TRAIP regulating the replication response to topoisomerase inhibitors. Glad to have been a part of it. www.nature.com/articles/s41...

What a legend. Such a shame.

BRCA2 C-terminal clamp restructures RAD51 dimers to bind B-DNA for replication fork stability With detailed structural and molecular analyses, Longo et al. find that the BRCA2 C-terminal TR2, which is a critical cancer therapy resistance factor, reshapes the RAD51 dimer for B-DNA binding that is incompatible with double-strand break repair interactions but activates it in DNA replication fork protection.

BRCA2 C-terminal clamp restructures RAD51 dimers to bind B-DNA for replication fork stability

USP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP

We are looking to recruit three posts at the @crick.ac.uk in structural biology, cell biology, and pharmacology to join a 20+ strong multidisciplinary team focused on delivering the first precision medicines for the treatment of ALT cancers. Interested? Please check out the advertised jobs below:

ARID1A stabilises non-homologous end joining factors at DNA breaks induced by the G4 ligand pyridostatin ARID1A is a subunit of the BAF chromatin remodelling complex that is frequently mutated in cancer. It is challenging to predict how ARID1A loss impacts cancer therapy response because it participates ...

New preprint from the lab on ARID1A, G quadruplexes, and repair:
www.biorxiv.org/content/10.1...

Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish - Scientific Reports Scientific Reports - Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish

Loss of XRCC1 disrupts cerebellar development in zebrafish due to toxic PARP1 accumulation. Strikingly, parp1 knockdown rescues the XRCC1 phenotype, supporting PARP1 inhibition as a potential therapy in recessive XRCC1-related neurodegenerative disorders with ataxia. www.nature.com/articles/s41...

Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin - Nature Communications DNA double strand break repair pathways ensure genome stability and prevent disease. Here the authors show that the actin nucleating factor DIAPH1 and γ-actin promote homologous recombination (HR)-dep...

Proud to present our work identifying a role for DIAPH1 and gamma-actin in regulating DSB repair and how defects in this pathway give rise to human disease. Big thanks to everyone involved, especially Beth Woodward, Sudipta Lahiri and @anoopsinghchauhan.bsky.social. www.nature.com/articles/s41...

53BP1/RIF1 and DNA-PKcs show distinct genetic interactions with diverse chromosomal break repair outcomes. DNA double strand breaks (DSBs) are the effective lesion of cancer radiotherapy and induce gene editing. 53BP1 accumulates at DSBs and is implicated in end joining (EJ) repair, but its influence on DS...

New preprint from the lab @kaelamakins.bsky.social Genetic interactions between 53BP1-RIF1 and DNA-PKcs for DSB repair outcomes. 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...

Another win for Birmingham!

PIN1-SUMO2/3 motif suppresses excessive RNF168 chromatin accumulation and ubiquitin signaling to promote IR resistance - Nature Communications The ubiquitin ligase, RNF168, promotes DNA break repair but must be regulated to prevent run-away ubiquitin signaling. Here, the authors identify a three-step post-translational cascade regulating RNF...

📢 Just published! Excited to share my latest research, now published in Nature Communications! Grateful to my collaborators and mentors who made this work possible.
@profstewartlab.bsky.social @Jo Morris, @Aneika C. Leney, @drjhujh.bsky.social

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

Research Fellow at University of Birmingham Discover an exciting academic career path as a Research Fellow at jobs.ac.uk. Don't miss out on this job opportunity - apply today!

My lab is #hiring!

I am recruiting for two #Postdoc positions investigating the Alternative Lengthening of Telomeres mechanism.

www.jobs.ac.uk/job/DLO693/r...

www.jobs.ac.uk/job/DLP016/r...

#Telomere #DNAreplication #DNArepair #cancer #glioma #UKRI #MRC #universityofbirmingham #NGS

The Shu complex –a conserved homologous recombination factor– interact with ORC and MCM replication initiation factors to facilitate error-free bypass of replicative DNA damage
Kara Bernstein, Katrin Paeschke and coworkers
www.embopress.org/doi/full/10....

Happy to share our new review with Chiara Fiorenzani and Adele Mossa published on @cp-trendsgenetics.bsky.social
🧬 🧠

This work is dedicated to the loving memory of Dr. Daniele Di Marino ❤️

urldefense.proofpoint.com/v2/url?u=htt...

Chen, Wu, Li, Li, et al. (Chongqing Medical University) report that DEK accumulates in Fancd2−/− HSCs and CD34⁺ cells from patients with Fanconi anemia, causing #chromatin relaxation failure under replication stress. https://buff.ly/40IoKSQ

#Hematopoiesis

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

Identification of critical factors of the replication stress response in human cells https://www.biorxiv.org/content/10.1101/2025.01.12.632149v1