Imperial College London

DrMarcoDi Antonio

Faculty of Natural SciencesDepartment of Chemistry

Advanced Research Fellow (BBSRC Fellow)
 
 
 
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Contact

 

+44 (0)20 7594 5866m.di-antonio

 
 
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Location

 

207LMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

38 results found

Di Antonio M, Ponjavic A, Radzevičius A, Ranasinghe RT, Catalano M, Zhang X, Shen J, Needham L-M, Lee SF, Klenerman D, Balasubramanian Set al., 2020, Single-molecule visualization of DNA G-quadruplex formation in live cells., Nature Chemistry, Vol: 12, Pages: 832-837, ISSN: 1755-4330

Substantial evidence now exists to support that formation of DNA G-quadruplexes (G4s) is coupled to altered gene expression. However, approaches that allow us to probe G4s in living cells without perturbing their folding dynamics are required to understand their biological roles in greater detail. Herein, we report a G4-specific fluorescent probe (SiR-PyPDS) that enables single-molecule and real-time detection of individual G4 structures in living cells. Live-cell single-molecule fluorescence imaging of G4s was carried out under conditions that use low concentrations of SiR-PyPDS (20 nM) to provide informative measurements representative of the population of G4s in living cells, without globally perturbing G4 formation and dynamics. Single-molecule fluorescence imaging and time-dependent chemical trapping of unfolded G4s in living cells reveal that G4s fluctuate between folded and unfolded states. We also demonstrate that G4 formation in live cells is cell-cycle-dependent and disrupted by chemical inhibition of transcription and replication. Our observations provide robust evidence in support of dynamic G4 formation in living cells.

Journal article

Minard A, Morgan D, Raguseo F, Di Porzio A, Liano D, Jamieson AG, Di Antonio Met al., 2020, A short peptide that preferentially binds c-MYC G-quadruplex DNA, CHEMICAL COMMUNICATIONS, Vol: 56, Pages: 8940-8943, ISSN: 1359-7345

Journal article

Chung BYW, Balcerowicz M, Di Antonio M, Jaeger KE, Geng F, Franaszek K, Marriott P, Brierley I, Firth AE, Wigge PAet al., 2020, An RNA thermoswitch regulates daytime growth in Arabidopsis, NATURE PLANTS, Vol: 6, Pages: 522-+, ISSN: 2055-026X

Journal article

Raguseo F, Chowdhury S, Minard A, Di Antonio Met al., 2020, Chemical-biology approaches to probe DNA and RNA G-quadruplex structures in the genome, CHEMICAL COMMUNICATIONS, Vol: 56, Pages: 1317-1324, ISSN: 1359-7345

Journal article

Weber J, Bollepalli L, Belenguer AM, Di Antonio M, De Mitri N, Joseph J, Balasubramanian S, Hunter CA, Bohndiek SEet al., 2019, An Activatable Cancer-Targeted Hydrogen Peroxide Probe for Photoacoustic and Fluorescence Imaging, CANCER RESEARCH, Vol: 79, Pages: 5407-5417, ISSN: 0008-5472

Journal article

Zyner KG, Mulhearn DS, Adhikari S, Cuesta SM, Di Antonio M, Erard N, Hannon GJ, Tannahill D, Balasubramanian Set al., 2019, Genetic interactions of G-quadruplexes in humans, ELIFE, Vol: 8, ISSN: 2050-084X

Journal article

Di Antonio M, Minard A, Liano D, Wang Xet al., 2019, The unexplored potential of quinone methides in chemical biology, Bioorganic and Medicinal Chemistry, Vol: 27, Pages: 2298-2305, ISSN: 0968-0896

Quinone methides (QMs) are transient reactive species that can be efficiently generated from stable precursors under a variety of biocompatible conditions. Due to their electrophilic nature, QMs have been widely explored as cross-linking agents of DNA and proteins under physiological conditions. However, QMs also have a diene character and can irreversibly react via Diels-Alder reaction with electron-rich dienophiles. This particular reactivity has been recently exploited to label biomolecules with fluorophores in living cells.QMs are characterised by two unique properties that make them ideal candidates for chemical biology applications: i) they can be efficiently generated in situ from very stable precursors by means of bio-orthogonal protocols ii) they are reversible cross-linking agents, making them suitable for “catch and release” target-enrichment experiments. Nevertheless, there are only few examples reported to date that truly take advantage of QMs unique chemistry in the context of chemical-biology assay development. In this review, we will examine the most relevant examples that illustrate the benefit of using QMs for chemical biology purposes and we will anticipate novel approaches to further their applications in biologically relevant contexts.

Journal article

Marsico G, Chambers VS, Sahakyan AB, McCauley P, Boutell JM, Antonio MD, Balasubramanian Set al., 2019, Whole genome experimental maps of DNA G-quadruplexes in multiple species, Nucleic Acids Research, Vol: 47, Pages: 3862-3874, ISSN: 0305-1048

Genomic maps of DNA G-quadruplexes (G4s) can help elucidate the roles that these secondary structures play in various organisms. Herein, we employ an improved version of a G-quadruplex sequencing method (G4-seq) to generate whole genome G4 maps for 12 species that include widely studied model organisms and also pathogens of clinical relevance. We identify G4 structures that form under physiological K+ conditions and also G4s that are stabilized by the G4-targeting small molecule pyridostatin (PDS). We discuss the various structural features of the experimentally observed G-quadruplexes (OQs), highlighting differences in their prevalence and enrichment across species. Our study describes diversity in sequence composition and genomic location for the OQs in the different species and reveals that the enrichment of OQs in gene promoters is particular to mammals such as mouse and human, among the species studied. The multi-species maps have been made publicly available as a resource to the research community. The maps can serve as blueprints for biological experiments in those model organisms, where G4 structures may play a role.

Journal article

Sengar A, Vandana JJ, Chambers VS, Di Antonio M, Winnerdy FR, Balasubramanian S, Anh TPet al., 2019, Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter, NUCLEIC ACIDS RESEARCH, Vol: 47, Pages: 1564-1572, ISSN: 0305-1048

Journal article

Mao S-Q, Ghanbarian AT, Spiegel J, Cuesta SM, Beraldi D, Di Antonio M, Marsico G, Hansel-Hertsch R, Tannahill D, Balasubramanian Set al., 2018, DNA G-quadruplex structures mold the DNA methylome, Nature Structural and Molecular Biology, Vol: 25, Pages: 951-957, ISSN: 1545-9985

Control of DNA methylation level is critical for gene regulation, and the factors that govern hypomethylation at CpG islands (CGIs) are still being uncovered. Here, we provide evidence that G-quadruplex (G4) DNA secondary structures are genomic features that influence methylation at CGIs. We show that the presence of G4 structure is tightly associated with CGI hypomethylation in the human genome. Surprisingly, we find that these G4 sites are enriched for DNA methyltransferase 1 (DNMT1) occupancy, which is consistent with our biophysical observations that DNMT1 exhibits higher binding affinity for G4s as compared to duplex, hemi-methylated, or single-stranded DNA. The biochemical assays also show that the G4 structure itself, rather than sequence, inhibits DNMT1 enzymatic activity. Based on these data, we propose that G4 formation sequesters DNMT1 thereby protecting certain CGIs from methylation and inhibiting local methylation.

Journal article

Greenfield JL, Evans EW, Di Nuzzo D, Di Antonio M, Friend RH, Nitschke JRet al., 2018, Unraveling Mechanisms of Chiral Induction in Double-Helical Metallopolymers, Journal of the American Chemical Society, Vol: 140, Pages: 10344-10353, ISSN: 0002-7863

© 2018 American Chemical Society. Self-assembled helical polymers hold great promise as new functional materials, where helical handedness controls useful properties such as circularly polarized light emission or electron spin. The technique of subcomponent self-assembly can generate helical polymers from readily prepared monomers. Here we present three distinct strategies for chiral induction in double-helical metallopolymers prepared via subcomponent self-assembly: (1) employing an enantiopure monomer, (2) polymerization in a chiral solvent, (3) using an enantiopure initiating group. Kinetic and thermodynamic models were developed to describe the polymer growth mechanisms and quantify the strength of chiral induction, respectively. We found the degree of chiral induction to vary as a function of polymer length. Ordered, rod-like aggregates more than 70 nm long were also observed in the solid state. Our findings provide a basis to choose the most suitable method of chiral induction based on length, regiochemical, and stereochemical requirements, allowing stereochemical control to be established in easily accessible ways.

Journal article

Sahakyan AB, Chambers VS, Marsico G, Santner T, Di Antonio M, Balasubramanian Set al., 2017, Machine learning model for sequence-driven DNA G-quadruplex formation, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

Journal article

Hansel-Hertsch R, Di Antonio M, Balasubramanian S, 2017, DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential, NATURE REVIEWS MOLECULAR CELL BIOLOGY, Vol: 18, Pages: 279-284, ISSN: 1471-0072

Journal article

Nieto-Orellana A, Di Antonio M, Conte C, Falcone FH, Bosquillon C, Childerhouse N, Mantovani G, Stolnik Set al., 2017, Effect of polymer topology on non-covalent polymer-protein complexation: miktoarm versus linear mPEG-poly(glutamic acid) copolymers, POLYMER CHEMISTRY, Vol: 8, Pages: 2210-2220, ISSN: 1759-9954

Journal article

Xu H, Di Antonio M, McKinney S, Mathew V, Ho B, O'Neil NJ, Dos Santos N, Silvester J, Wei V, Garcia J, Kabeer F, Lai D, Soriano P, Banath J, Chiu DS, Yap D, Le DD, Ye FB, Zhang A, Thu K, Soong J, Lin S-C, Tsai AHC, Osako T, Algara T, Saunders DN, Wong J, Xian J, Bally MB, Brenton JD, Brown GW, Shah SP, Cescon D, Mak TW, Caldas C, Stirling PC, Hieter P, Balasubramanian S, Aparicio Set al., 2017, CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours, Nature Communications, Vol: 8, Pages: 1-18, ISSN: 2041-1723

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).

Journal article

Nicoli F, Roos MK, Hemmig EA, Di Antonio M, de Vivie-Riedle R, Liedl Tet al., 2016, Proximity-Induced H-Aggregation of Cyanine Dyes on DNA-Duplexes, JOURNAL OF PHYSICAL CHEMISTRY A, Vol: 120, Pages: 9941-9947, ISSN: 1089-5639

Journal article

Hansel-Hertsch R, Beraldi D, Lensing SV, Marsico G, Zyner K, Parry A, Di Antonio M, Pike J, Kimura H, Narita M, Tannahill D, Balasubramanian Set al., 2016, G-quadruplex structures mark human regulatory chromatin, Nature Genetics, Vol: 48, Pages: 1267-1272, ISSN: 1061-4036

G-quadruplex (G4) structural motifs have been linked to transcription1,2, replication3 and genome instability4,5 and are implicated in cancer and other diseases6,7,8. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context9,10. Herein we address this through the development of G4 ChIP–seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5′ UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor–induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.

Journal article

Chambers VS, Marsico G, Boutell JM, Di Antonio M, Smith GP, Balasubramanian Set al., 2015, High-throughput sequencing of DNA G-quadruplex structures in the human genome, Nature Biotechnology, Vol: 33, Pages: 877-881, ISSN: 1087-0156

G-quadruplexes (G4s) are nucleic acid secondary structures that form within guanine-rich DNA or RNA sequences. G4 formation can affect chromatin architecture and gene regulation and has been associated with genomic instability, genetic diseases and cancer progression1,2,3,4. Here we present a high-resolution sequencing–based method to detect G4s in the human genome. We identified 716,310 distinct G4 structures, 451,646 of which were not predicted by computational methods5,6,7. These included previously uncharacterized noncanonical long loop and bulged structures8,9. We observed a high G4 density in functional regions, such as 5′ untranslated regions and splicing sites, as well as in genes previously not predicted to contain these structures (such as BRCA2). G4 formation was significantly associated with oncogenes, tumor suppressors and somatic copy number alterations related to cancer development10. The G4s identified in this study may therefore represent promising targets for cancer intervention.

Journal article

Yangyuoru PM, Di Antonio M, Ghimire C, Biffi G, Balasubramanian S, Mao Het al., 2015, Dual Binding of an Antibody and a Small Molecule Increases the Stability of TERRA G-Quadruplex, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 54, Pages: 910-913, ISSN: 1433-7851

Journal article

Yangyuoru PM, DiAntonio M, Ghimire C, Biffi G, Balasubramanian S, Mao Het al., 2015, Dual Binding of an Antibody and a Small Molecule Increases the Stability of TERRA G-Quadruplex, Angewandte Chemie, Vol: 127, Pages: 924-927, ISSN: 0044-8249

Journal article

Le DD, Di Antonio M, Chan LKM, Balasubramanian Set al., 2015, G-quadruplex ligands exhibit differential G-tetrad selectivity, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 8048-8050, ISSN: 1359-7345

Journal article

Di Antonio M, McLuckie KIE, Balasubramanian S, 2014, Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a G-Quadruplex Ligand, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 136, Pages: 5860-5863, ISSN: 0002-7863

Journal article

Biffi G, Di Antonio M, Tannahill D, Balasubramanian Set al., 2014, Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells, NATURE CHEMISTRY, Vol: 6, Pages: 75-80, ISSN: 1755-4330

Journal article

Di Antonio M, 2014, Quinone Methides Generation: Applications in Chemical Biology, CURRENT ORGANIC CHEMISTRY, Vol: 18, Pages: 2-2, ISSN: 1385-2728

Journal article

McLuckie KIE, Di Antonio M, Zecchini H, Xian J, Caldas C, Krippendorff B-F, Tannahill D, Lowe C, Balasubramanian Set al., 2013, G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 135, Pages: 9640-9643, ISSN: 0002-7863

Journal article

Mitchell T, Ramos-Montoya A, Di Antonio M, Murat P, Ohnmacht S, Micco M, Jurmeister S, Fryer L, Balasubramanian S, Neidle S, Neal DEet al., 2013, Downregulation of Androgen Receptor Transcription by Promoter G-Quadruplex Stabilization as a Potential Alternative Treatment for Castrate-Resistant Prostate Cancer, BIOCHEMISTRY, Vol: 52, Pages: 1429-1436, ISSN: 0006-2960

Journal article

Murat P, Gormally MV, Sanders D, Di Antonio M, Balasubramanian Set al., 2013, Light-mediated in cell downregulation of G-quadruplex-containing genes using a photo-caged ligand, CHEMICAL COMMUNICATIONS, Vol: 49, Pages: 8453-8455, ISSN: 1359-7345

Journal article

Nikan M, Di Antonio M, Abecassis K, McLuckie K, Balasubramanian Set al., 2013, An Acetylene-Bridged 6,8-Purine Dimer as a Fluorescent Switch-On Probe for Parallel G-Quadruplexes, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 52, Pages: 1428-1431, ISSN: 1433-7851

Journal article

Di Antonio M, Rodriguez R, Balasubramanian S, 2012, Experimental approaches to identify cellular G-quadruplex structures and functions, METHODS, Vol: 57, Pages: 84-92, ISSN: 1046-2023

Journal article

Doria F, Nadai M, Folini M, Di Antonio M, Germani L, Percivalle C, Sissi C, Zaffaroni N, Alcaro S, Artese A, Richter SN, Freccero Met al., 2012, Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 10, Pages: 2798-2806, ISSN: 1477-0520

Journal article

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