Grant Stewart

Grant Stewart

@profstewartlab.bsky.social

Group leader at the University of Birmingham interested in rare diseases caused by inherited defects in DNA repair and replication. Amateur geologist/palaeontologist and shark enthusiast.

718 followers265 following20 posts

Grant Stewart
@profstewartlab.bsky.social

Amazing collaboration with the @andrewblackford.bsky.social @fenaochs.bsky.social and Zafar Iqbal on the identification of DDIAS as a new mitotic repair factor that is mutated in a novel chromosomal instability syndrome. www.cell.com/cell/fulltex...

cell.comDDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain developmentDDIAS is identified as a factor that protects single-stranded DNA during mitosis to maintain chromosome stability, and inactivating mutations in DDIAS are identified in a human neurodevelopmental diso...
Grant Stewart
@profstewartlab.bsky.social

Finally our collaborative paper on inherited mutations in the actin nulceating factor, DIAPH1, spear-headed by the Houlden lab, @reza-maroofian.bsky.social, Valentina Galassi Deforie, Stephanie Efthymiou and Peter Arkwright, is out in Genetics in Medicine. www.gimjournal.org/article/S109...

gimjournal.orgRecessive Loss of DIAPH1 Function Causes a Progressive Neurodevelopmental Syndrome with Variable Immunological InvolvementBiallelic DIAPH1 pathogenic variants cause a neurodevelopmental syndrome occasionally associated with immunodeficiency. This study aims to define the clinical and immunological spectrum of DIAPH1-rela...

Grant Stewart reposted

Molecular Cell
@cp-molcell.bsky.social

Online Now: IFI16 senses and protects stalled replication forks Online now:

dlvr.itIFI16 senses and protects stalled replication forksGamble et al. demonstrate that detection of stalled replication forks by the innate immune sensor IFI16 induces an early STING-dependent pro-inflammatory cytokine response independently of cGAS and DNA damage. Furthermore, IFI16 exhibits dual functionality during replication stress by protecting stalled, remodeled replication forks from nucleolytic degradation.
Grant Stewart
@profstewartlab.bsky.social

Awesome collaboration with @SPJacksonGroup, @drjhujh.bsky.social, Chris Carney and Soren Hough, understanding how inherited mutations in the MEAE E3 ubiquitin ligase causes disease by compromising HR-dependent replication fork protection/restart. link.springer.com/article/10.1...

link.springer.comLoss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay - EMBO Molecular MedicineUbiquitin E3 ligases play crucial roles in the DNA damage response (DDR) by modulating the turnover, localization, activation, and interactions of DDR and DNA replication proteins. We performed a CRIS...

Grant Stewart reposted

María Fernández-Casañas
@emefece.bsky.social

Our @costerlab.bsky.social review is out! It’s a great read on the impact of DNA secondary structures on eukaryotic replication fork progression - a totally unbiased opinion, of course! www.sciencedirect.com/science/arti... @adityasethi.bsky.social @billiedelpino.bsky.social

sciencedirect.comHow DNA secondary structures drive replication fork instabilityDNA secondary structures, such as hairpins, cruciforms, triplexes, G-quadruplexes and iMotifs, are common, dynamic features that replication forks rou…

Grant Stewart reposted

Alberto Marin
@albertomarin.bsky.social

Thrilled to share that my postdoc research is published today in @science.org! We found that DNA repair uses cohesin complexes to build new chromatin loops that guide the homology search and boost accurate repair! 1/n www.science.org/doi/10.1126/...

science.orgCohesin drives chromatin scanning during the RAD51-mediated homology searchCohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop bas...
Grant Stewart
@profstewartlab.bsky.social

Interested in inherited chromosomal instability syndromes and DNA repair? We are looking for an enthusiastic person to join the Stewart lab at the University of Birmingham as a senior technician. Please checkout the job advert: www.jobs.ac.uk/job/DPH515/senior-research-technician

jobs.ac.ukSenior Research Technician at University of BirminghamAn academic position as a Senior Research Technician is being advertised on jobs.ac.uk. Click now to find more details and explore additional academic job opportunities.

Grant Stewart reposted

Lopes_Lab
@lopeslab.bsky.social

Happy to have contributed to this interesting study from penengolab.bsky.social! another interesting example of how chromatin modifications and their readers orchestrate replication fork plasticity and protection 👏👇

The EMBO Journal@embojournal.org

H2B ubiquitination by RNF20/40 safeguards replication fork dynamics in human cells, by facilitating fork reversal and recruiting RNF169 that protects from excessive degradation of nascent DNA @penengolab.bsky.social and collaborators www.embopress.org/doi/full/10....

Grant Stewart reposted

Shicheng Guo
@shihcheng.bsky.social

RNA:DNA hybrids increase at DSBs, crucial for repair, but form without RNA polymerase recruitment. Discover insights on hybrid accumulation. PMID:40447771, Nat Cell Biol 2025, @NatureCellBio https://doi.org/10.1038/s41556-025-01669-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgTranscriptional repression facilitates RNA:DNA hybrid accumulation at DNA double-strand breaks | Nature Cell BiologyRNA:DNA hybrids accumulate at DNA double-strand breaks (DSBs) and were shown to regulate homologous recombination repair. The mechanism responsible for the formation of these non-canonical RNA:DNA structures remains unclear although they were proposed to arise consequently to RNA polymerase II or III loading followed by DSB-induced de novo transcription at the break site. Here, we found no evidence of RNA polymerase recruitment at DSBs. Rather, strand-specific R-loop mapping revealed that RNA:DNA hybrids are mainly generated at DSBs occurring in transcribing loci, from the hybridization of pre-existing RNA to the 3′ overhang left by DNA end resection. We further identified the H3K4me3 reader spindlin 1 and the transcriptional regulator PAF1 as factors promoting RNA:DNA hybrid accumulation at DSBs, through their role in mediating transcriptional repression in cis to DSBs. Altogether, we provide evidence that RNA:DNA hybrids accumulate at DSBs occurring in transcribing loci as a result o

Grant Stewart reposted

Petr Cejka
@cejkalab.bsky.social

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...

Grant Stewart reposted

Fena Ochs
@fenaochs.bsky.social

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...

biorxiv.orgDDIAS is a single-stranded DNA-binding effector of the TOPBP1-CIP2A complex in mitosisDNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segre...
Grant Stewart
@profstewartlab.bsky.social

Great work by the Kitagawa lab about DONSON regulating centrosome duplication is finally out in Nature Comms www.nature.com/articles/s41...

nature.comThe DNA replication machinery transmits dual signals to prevent unscheduled licensing and execution of centrosome duplication - Nature CommunicationsCell division requires strict control of DNA replication and centrosome duplication. Here, the authors reveal that DNA replication machinery transmits dual signals to control proper timing of centroso...
Grant Stewart
@profstewartlab.bsky.social

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...

nature.comThe RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling - Nature CommunicationsDNA 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...

Grant Stewart reposted

Niels Keijzer
@nkeijzer.bsky.social

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...

doi.orgUSP1/UAF1 targets polyubiquitinated PCNA with an exo-cleavage mechanism that can temporarily enrich for monoubiquitinated PCNA - Nature CommunicationsDNA 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...

Grant Stewart reposted

Molecular Cell
@cp-molcell.bsky.social

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

dlvr.itThe DNA replication checkpoint limits Okazaki fragment accumulation to protect and restart stalled forksCanal 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.

Grant Stewart reposted

Andrew Blackford
@andrewblackford.bsky.social

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...

candidate.hr-manager.netPostdoctoral Research Associate in the Blackford GroupA position as Postdoctoral Research Associate is available at the Department of Cellular and Molecular Medicine, in the group headed by Dr. Andrew Blackford. Th
Grant Stewart
@profstewartlab.bsky.social

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...

nature.comUSP37 prevents premature disassembly of stressed replisomes by TRAIP - Nature CommunicationsThe 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...

Grant Stewart reposted

Molecular Cell
@cp-molcell.bsky.social

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

dlvr.itBRCA2 C-terminal clamp restructures RAD51 dimers to bind B-DNA for replication fork stabilityWith 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.

Grant Stewart reposted

Cell Reports
@cp-cellreports.bsky.social

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

dlvr.itUSP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIPVilla et al. show that the USP37 deubiquitylase is tethered to the CMG helicase at DNA replication forks in mammalian cells. USP37 protects cells during DNA replication stress by counteracting two replisome-coupled ubiquitin ligases. USP37 counteracts CUL2LRR1 during DNA synthesis defects and opposes TRAIP in response to topological stress.

Grant Stewart reposted

Boulton Lab
@boultonlab.bsky.social

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:

Grant Stewart reposted

Reza Maroofian
@reza-maroofian.bsky.social

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...

nature.comParp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish - Scientific ReportsScientific Reports - Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish
Grant Stewart
@profstewartlab.bsky.social

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...

nature.comInherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin - Nature CommunicationsDNA 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...

Grant Stewart reposted

JStark lab
@jstarklab.bsky.social

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...

biorxiv.org53BP1/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...

Grant Stewart reposted

Anoop Chauhan
@anoopsinghchauhan.bsky.social

📢 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...

nature.comPIN1-SUMO2/3 motif suppresses excessive RNF168 chromatin accumulation and ubiquitin signaling to promote IR resistance - Nature CommunicationsThe 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...

Grant Stewart reposted

Ronan Broderick
@brodericklab.bsky.social

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

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

Grant Stewart reposted

Cantorlab
@cantorlab.bsky.social

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

rdcu.beTargeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerabilityNature 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...

Grant Stewart reposted

Tony Cesare
@thecesarelab.bsky.social

1/Delighted to announce the newest paper from our lab, “Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage”, is out today in @naturecellbiology.bsky.social, www.nature.com/articles/s41....

nature.comHomologous recombination promotes non-immunogenic mitotic cell death upon DNA damage - Nature Cell BiologySzmyd et al. show that DNA repair pathways impact whether cells with DNA lesions arrest in mitosis. The formation of homologous recombination-driven double Holliday junctions elicits mitotic cell deat...
Grant Stewart
@profstewartlab.bsky.social

Great paper about p38 and endometrial cancer from a long-term collaborator and friend, Cyrus Vaziri, just published in Cell Reports: www.cell.com/cell-reports...

cell.comMAPK14/p38α shapes the molecular landscape of endometrial cancer and promotes tumorigenic characteristicsUsing unbiased CRISPR-Cas9-based genetic screens, Joseph et al. identify MAPK14/p38α as a dependency and vulnerability of high-grade endometrial cancer (HGEC) metastatic spheroids. MAPK14/p38α critically programs the phosphoproteome, transcriptome, and metabolome of HGEC spheroids, promoting cancer stemness and tumorigenicity.

Grant Stewart reposted

Harvard Med Cell Biology
@harvardcellbio.bsky.social

New exciting work from the Chouchani Lab @harvardcellbio.bsky.social reports a global analysis of the zinc binding cysteine proteome. www.cell.com/cell/fulltex...

cell.comThe human zinc-binding cysteine proteomeA deep mapping of the human zinc-binding cysteine proteome (ZnCPT) defines thousands of zinc-binding protein cysteines across major domains of biology and discovers glutathione reductase as zinc-targetable cancer vulnerability.

Grant Stewart reposted

Titia Sixma
@titiasixma.bsky.social

Despite the black picture below, we're really happy to have this illuminating story online! Careful molecular mechanistic from Niels and others in the lab work giving unexpected biological insight!

Niels Keijzer@nkeijzer.bsky.social

Excited to share our new paper! Here we reveal USP1/UAF1 as a highly efficient DUB for K63- and K48 polyubiquitinated PCNA and give detailed insights into its mechanism that may drive pathway choice in DNA damage tolerance. Preprint is available now: www.biorxiv.org/content/10.1...

biorxiv.orgUSP1/UAF1 targets polyubiquitinated PCNA with an exo-cleavage mechanism that enriches for monoubiquitinated PCNADNA damage tolerance (DDT) is an important pathway that allows our cells to bypass DNA lesions during replication. DDT is orchestrated by ubiquitination of PCNA: Monoubiquitination (PCNA-Ub) initiates...

Grant Stewart reposted

semirkin.bsky.social
@semirkin.bsky.social

Another week, another great paper! Kudos to the amazing grad student, Chiara Masnovo who single-handedly initiated and led the project, and arranged a terrific collaboration with the Aharoni lab from Ben-Gurion University, and to the great members of the two labs. www.nature.com/articles/s41...?

nature.comStabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability - Nature CommunicationsDNA 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, counteracts instability of G...

Grant Stewart reposted

Daniel Durocher
@durocher1.bsky.social

Review on synthetic lethal strategies in oncology, with a small contribution from yours truly. www.nature.com/articles/s41...

nature.comSynthetic lethal strategies for the development of cancer therapeutics - Nature Reviews Clinical OncologyThe 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....

Grant Stewart reposted

marcelvanvugt.bsky.social
@marcelvanvugt.bsky.social

Happy to share our study by Francien Talens and many colleagues on RAD51 foci formation as a functional marker for PARPi sensitivity in ovarian cancer PDX models. academic.oup.com/narcancer/ar...

academic.oup.comRAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer patient-derived xenograft modelsAbstract. Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been at

Grant Stewart reposted

Julian Stingele
@jstingele.bsky.social

Happy to share our latest work🍾 🥳 PhD student Sophie Dürauer discovered together with many wonderful collaborators that the ubiquitylation of DNA-protein crosslinks promotes their cleavage by SPRTN more than 100-fold 🧬🔧

bioRxiv Biochemistry@biorxiv-biochem.bsky.social

Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability https://www.biorxiv.org/content/10.1101/2024.11.26.625192v1

biorxiv.orgAllosteric activation of the SPRTN protease by ubiquitin maintains genome stability https://www.biorxiv.org/content/10.1101/2024.11.26.625192v1 The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslink

Grant Stewart reposted

Simon Bekker-Jensen lab
@bekkerjensenlab.bsky.social

Time for our first post here 🥳 Our latest paper is online 🙌 We show that UV activates the ribotoxic stress response, which causes inflammation, cell death and thickening in skin. Read about a role for the RSR separate from DNA damage signaling in response to sunburn: ✨☀️ www.cell.com/molecular-ce...

cell.comThe ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivoThe acute skin reaction to sunburn, encompassing keratinocyte cell death, inflammation, and epidermal thickening, has traditionally been ascribed to DNA damage responses. Using a mouse model deficient...

Grant Stewart reposted

Micha Rapé Lab
@micharapelab.bsky.social

Excited to report our discovery of an important component of the oxidative stress response: the E3 ligase TRIP12. It acts as a chain elongation factor that amplifies CUL3-KEAP1 activity to drive NRF2 degradation as cells recover from stress. www.biorxiv.org/content/10.1...

biorxiv.orgDynamic regulation of the oxidative stress response by the E3 ligase TRIP12The oxidative stress response is centered on the transcription factor NRF2 and protects cells from reactive oxygen species (ROS). While ROS inhibit the E3 ligase CUL3-KEAP1 to stabilize NRF2 and elici...