Genome Metabolism and Biostruct Research Group

Group Leader: Beáta Grolmuszné Vértessy PhD DSc

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Address: Szent Gellért tér 4. 1^st floor161-164, 241, and the Biostruct Laboratory, Budapest H-1111

2^nd address: Magyar Tudósok krt. 2. 3^rd floor, 3.D03, Institute of Molecular Life Sciences, Hun-Ren Research Center for Natural Sciences

Short introduction:

The primary focus of our research group is on the key mechanisms responsible for the maintenance of genomic integrity. In particular, we investigate the physiological processes underlying the formation, persistence, and removal of uracil in DNA. Uracil in DNA also has major pathophysiological relevance in several widespread diseases, including tuberculosis, malaria, and cancer. Consequently, our basic research activities are closely linked to biomedical applications, contributing to the identification of important drug targets and candidate therapeutic molecules.

Our cell biological studies extend to multiple animal model systems, including Drosophila melanogaster, zebrafish, and mouse models. For our in vitro mechanistic investigations, we employ a broad range of methods from structural and molecular biology.

The dynamic development of the group was initiated by the award of the prestigious Howard Hughes International Scholar grant, received for two consecutive five-year periods starting in 2001. Our group operates at two locations: the Institute of Molecular Life Sciences at HUN-REN RCNS (formerly the Institute of Enzymology) and the Department of Applied Biotechnology and Food Science at Budapest University of Technology and Economics (BME).

We place strong emphasis on the involvement of young researchers, including undergraduate and graduate students, PhD students, and postdoctoral fellows. Each year, approximately 5–6 award-winning undergraduate research (TDK) theses and numerous BSc and MSc theses are completed within the group, and 1–2 of our students typically obtain their PhD degree annually.

Members: Angéla Békési PhD, Gergely Nándor Nagy PhD, Kinga Nyíri PhD, Kinga Kelemenné Nagy Phd, Ákos Sveiczer PhD, Ibolya Leveles, Nikolett Emődi, András Telek, Otília Tóth, Viktória Berta Perey-Simon, Milda Blanka Szajkó

Members at HUN-REN RCNS: Judit Tóth, Rita Hirmondó, Hajnalka Laura Pálinkás, Nikolett Nagy, Zoé Sára Tóth, Eszter Holub, Eszter Oláh, Gergely Döbrőssy, Éva Tankó

Main research topics:

1. Investigating the potential roles of uracil in DNA and other non-canonical bases in chromatin organization and developmental biology

Uracil in DNA is a thymine analogue, a rare non-canonical base that can arise via two main mechanisms. First, during DNA replication, uracil may be incorporated in place of thymine if the intracellular nucleotide triphosphate balance permits. Second, cytosine residues in DNA may undergo oxidative deamination, either spontaneously or through enzyme-catalyzed processes, resulting in the formation of uracil. In the latter case, uracil carries altered genetic information: if left unrepaired, it leads to a fixed point mutation after the next round of replication.

An efficient DNA repair pathway has evolved to remove uracil from DNA; however, this pathway does not distinguish between the “innocent” uracil incorporated instead of thymine and the “mutagenic” uracil originating from cytosine deamination. Thymine-replacing incorporation is normally suppressed by maintaining a low intracellular dUTP/dTTP ratio, thereby minimizing futile DNA repair.

From the outset, our group has focused on situations in which uracil in DNA does not merely represent an error but instead fulfills a biological function. We have extensively studied the role of genomic uracil accumulation during the metamorphosis of holometabolous insects, demonstrating its involvement in developmental reprogramming (PMID: 14996835, 17306761, 22685418, 23238493). In addition, we detected substantial levels of uracil-containing DNA during early embryonic development in vertebrates (zebrafish) and characterized its distinctive genomic distribution, including co-localization with specific satellite DNA regions. This uracil content decreases dramatically by the time of zygotic genome activation. Both acceleration and delay of this process through microinjection of specific factors result in severe developmental defects and embryonic lethality.

2. Structural investigation of the role of dUTPase in cell division, its cellular interaction partners, and its dUTP-hydrolyzing activity

(Niki Nagy and Kinga Nyíri)

A bacterial Stl protein, originally identified as an interaction partner of a bacteriophage dUTPase, was recently shown to inhibit the enzymatic activity of dUTPases from a wide range of species (PMID: 25274731, 25841100, 29531348, 31174420). This makes Stl a promising tool for probing the cellular functions of dUTPase. By determining the crystal structures of dUTPase–Stl complexes (PDB: 8C8I, 8P8O) and analyzing the effects of modified Stl variants on the dUTPase reaction, we identified key molecular determinants of enzymatic inhibition and protein–protein interaction (PMID: 39511242, 39924564).

We are currently validating potential intracellular interaction partners of human dUTPase identified using the yeast two-hybrid system. In parallel, we investigate the role of dUTPase in cell division and embryonic development using human cell lines and mouse embryos. We demonstrated that mouse embryos lacking dUTPase as a result of CRISPR/Cas-mediated gene deletion die shortly after implantation (PMID: 30987342). Furthermore, expression analyses of mouse tissues revealed that dUTPase is present at high levels in brain tissue throughout all stages of embryonic development, suggesting a role in brain development and neural cell differentiation (PMID: 38849394).

In addition, our studies of mammalian dUTPase cellular functions led to the identification of two novel isoforms of the enzyme (PMID: 37173337).

3. Mechanism of action of anticancer therapies targeting thymidylate biosynthesis

Several chemotherapeutic agents used in cancer treatment target the cellular de novo thymidylate biosynthesis pathway. A key component of the complex mechanism of action of these drugs is the inhibition of dTMP synthesis, which leads to an increased intracellular dUTP/dTTP ratio. In actively proliferating cells, this imbalance results in elevated uracil incorporation into DNA during DNA synthesis.

Uracil in DNA can exert cytostatic and cytotoxic effects through multiple mechanisms. Enhanced DNA repair activity can generate DNA strand break intermediates, while uracil residues may also interfere with transcription or with the function of other DNA-binding proteins. Despite the widespread clinical use of these drugs, resistance is common, and their precise mechanisms of action remain incompletely understood.

In our group, we investigate genomic uracil patterns induced by two thymidylate synthase inhibitors (FdUR and RTX) in colorectal cancer cell lines. To this end, we developed the U-DNA-Seq method (PMID: 32956035). Genomic uracil patterns proved to be molecular fingerprints of cellular responses to drug treatment. In cells arrested in S phase, genomic uracil accumulation is most prominent in early-replicating regions, closely following the pattern of DNA synthesis.

The two drugs induce similar but distinct genomic uracil profiles, which are differentially influenced by the DNA repair capacity of the cells. In addition, we uncovered the mutagenic effects and reduced cytotoxicity of high-dose 5-FdUR treatment, contributing to a better understanding of drug resistance mechanisms.

4. Biosynthesis and sulfation of proteoglycans

Heparan sulfate and chondroitin sulfate glycosaminoglycans (HS and CS GAGs) are polysaccharides composed of repeating disaccharide units that, when attached to core proteins, form functional components of key extracellular matrix proteoglycans. These molecules are essential regulators of cellular and tissue-level homeostasis, participating in developmental processes, tissue regeneration, and disease progression through their dynamic interactions with signaling molecules, extracellular matrix components, and cell-surface receptors.

The functional diversity of heparan and chondroitin sulfates is generated by the remarkable variability of post-synthetic sulfation and epimerization modifications of the polysaccharide chains. As a recent example, in a study spanning protein structural analysis to experimental mouse models, we demonstrated that specific HS and CS interactions of the cell-surface guidance molecule Semaphorin-5A regulate the migration of neural progenitor cells in brain regions responsible for memory formation (PMID: 38548715; Nagy GN et al., 2024, Nature Communications).

Despite their importance, the biosynthesis of HS and CS GAGs and the vast number of structures that can be generated by their biosynthetic pathways remain poorly understood. Our research aims to achieve a deeper understanding of the enzymes that play key roles in HS/CS biosynthesis in both physiological and pathological processes. We investigate the specificity of enzyme-mediated polysaccharide modifications using an integrative approach that combines recombinant protein expression, enzyme activity assays, polysaccharide interaction studies, and structural biology methods (X-ray diffraction and cryo-EM). These studies are conducted in collaboration with a leading international glycomics research group, the Copenhagen Center for Glycomics (Denmark), which provides detailed analytical characterization of enzyme-modified HS and CS chains.

5. Biocatalysis and protein engineering

Biocatalysis has become a key enabling technology in the chemical industry, as enzymatic processes allow the efficient and sustainable production of valuable compounds. Industrial application of biocatalysis requires specialized expertise and interdisciplinary thinking. Our group collaborates with the Servier Research Institute to expand the company’s biocatalytic toolbox with novel enzymes and engineered variants.

We seek efficient biocatalysts for chemical reactions commonly used in the pharmaceutical industry, such as reductive amination and amide bond formation. Our research follows two main directions: enzyme discovery and enzyme engineering. In the discovery phase, we use bioinformatic approaches to identify potential biocatalysts from genomic and metagenomic databases, followed by recombinant expression and laboratory characterization of the enzymes. For industrial applications, naturally occurring enzymes often require further optimization through protein engineering to achieve sufficient activity or to withstand industrial process conditions.

Accordingly, our work includes the design, construction, and testing of focused variant libraries to accelerate the translation of enzymes toward industrial use. This project exemplifies the potential of academic–industrial collaborations to establish the fundamental knowledge base required for the development of greener technologies in the chemical industry.

6. Investigation of nucleotide metabolism as a target for antibacterial, antiviral, and anticancer therapies

7. Investigation of mycobacterial resistance mechanisms

Selected publications:

Nagy N, Hádinger N, Tóth O, Rácz GA, Pintér T, Gál Z, Urbán M, Gócza E, Hiripi L, Acsády L, Vértessy BG. Characterization of dUTPase expression in mouse postnatal development and adult neurogenesis. Sci Rep. 2024 Jun 7;14(1):13139. doi: 10.1038/s41598-024-63405-0. PMID: 38849394; PMCID: PMC11161619.
Pálinkás HL, Békési A, Róna G, Pongor L, Papp G, Tihanyi G, Holub E, Póti Á, Gemma C, Ali S, Morten MJ, Rothenberg E, Pagano M, Szűts D, Győrffy B, Vértessy BG. Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments. eLife. 2020 Sep 21;9:e60498. doi: 10.7554/eLife.60498. PMID: 32956035; PMCID: PMC7505663.
Molnár D, Surányi ÉV, Trombitás T, Füzesi D, Hirmondó R, Toth J. Genetic stability of Mycobacterium smegmatis under the stress of first-line antitubercular agents. Elife. 2024 Nov 20;13:RP96695. doi: 10.7554/eLife.96695. PMID: 39565350; PMCID: PMC11578590.
Nagy GN, Zhao XF, Karlsson R, Wang K, Duman R, Harlos K, El Omari K, Wagner A, Clausen H, Miller RL, Giger RJ, Jones EY. Structure and function of Semaphorin-5A glycosaminoglycan interactions. Nat Commun. 2024 Mar 28;15(1):2723. doi: 10.1038/s41467-024-46725-7. PMID: 38548715; PMCID: PMC10978931.
Telek A, Molnár Z, Takács K, Varga B, Grolmusz V, Tasnádi G, Vértessy BG. Discovery and biocatalytic characterization of opine dehydrogenases by metagenome mining. Appl Microbiol Biotechnol. 2024 Dec;108(1):101. doi: 10.1007/s00253-023-12871-z. Epub 2024 Jan 13. PMID: 38229296; PMCID: PMC10787698.
Róna G, Scheer I, Nagy K, Pálinkás HL, Tihanyi G, Borsos M, Békési A, Vértessy BG. Detection of uracil within DNA using a sensitive labeling method for in vitro and cellular applications. Nucleic Acids Res. 2016 Feb 18;44(3):e28. doi: 10.1093/nar/gkv977. Epub 2015 Oct 1. PMID: 26429970; PMCID: PMC4756853.
Nagy GN, Marton L, Contet A, Ozohanics O, Ardelean LM, Révész Á, Vékey K, Irimie FD, Vial H, Cerdan R, Vértessy BG. Corrigendum: Composite Aromatic Boxes for Enzymatic Transformations of Quaternary Ammonium Substrates. Angew Chem Int Ed Engl. 2015 Jul 27;54(31):8866. doi: 10.1002/anie.201505314. Erratum for: Angew Chem Int Ed Engl. 2014 Dec 1;53(49):13471-6. doi: 10.1002/anie.201408246. PMID: 26199125.
Muha V, Horváth A, Békési A, Pukáncsik M, Hodoscsek B, Merényi G, Róna G, Batki J, Kiss I, Jankovics F, Vilmos P, Erdélyi M, Vértessy BG. Uracil-containing DNA in Drosophila: stability, stage-specific accumulation, and developmental involvement. PLoS Genet. 2012;8(6):e1002738. doi: 10.1371/journal.pgen.1002738. Epub 2012 Jun 7. PMID: 22685418; PMCID: PMC3369950.
Pancsa R, Fichó E, Molnár D, Surányi ÉV, Trombitás T, Füzesi D, Lóczi H, Szijjártó P, Hirmondó R, Szabó JE, Tóth J. dNTPpoolDB: a manually curated database of experimentally determined dNTP pools and pool changes in biological samples. Nucleic Acids Res. 2022 Jan 7;50(D1):D1508-D1514. doi: 10.1093/nar/gkab910. PMID: 34643700; PMCID: PMC8728230.
Vértessy BG, Tóth J. Keeping uracil out of DNA: physiological role, structure and catalytic mechanism of dUTPases. Acc Chem Res. 2009 Jan 20;42(1):97-106. doi: 10.1021/ar800114w. PMID: 18837522; PMCID: PMC2732909.
Sveiczer A, Csikasz-Nagy A, Gyorffy B, Tyson JJ, Novak B. Modeling the fission yeast cell cycle: quantized cycle times in wee1- cdc25Delta mutant cells. Proc Natl Acad Sci USA. 2000 Jul 5;97(14):7865-70. doi: 10.1073/pnas.97.14.7865. PMID: 10884416; PMCID: PMC16636.

Selected Achievements and Honors

2001–2005 and 2006–2010 – Howard Hughes International Research Scholar (Howard Hughes Medical Institute, USA)
2007 – Welcome Award (Biostruct Laboratory)
2008–2013 – NIH/Fogarty International Center GRIP Grant

G. Beáta Vértesy:

1998–2001 – János Bolyai Research Fellowship
2000 – Scientia Europaea Award (Institut de France and Aventis)
2004 – Qualitas Biologica Award, 1st Prize (Hungarian Academy of Sciences)
2012 – For Women in Science Award (L’Oréal–UNESCO)
2015 – Master Teacher Gold Medal (National Scientific Students’ Associations Conference – OTDT)
2016 – Béla Tankó Award (Hungarian Biochemical Society – MBKE)
2021 – Member of Academia Europaea
2022 – Corresponding Member of the Hungarian Academy of Sciences
2023 – Officer’s Cross of the Order of Merit of Hungary
2024 – Diplôme d’Honneur (FEBS)

Awards and Fellowships of Group Members:

Academic Youth Awards: Angéla Békési (2005), Judit Tóth (2008), …
János Bolyai Research Fellowships: Judit Tóth (2009–2012; 2016–2019), Angéla Békési (2022–2025), Gergely Nagy (2024–2027)
Bolyai Medal: Judit Tóth (2019)
OTDT “For Knowledge for Hungary” Commemorative Medal: Ákos Sveiczer (2001)
TDK Commemorative Medal for Student Research Supervision (BME): Ákos Sveiczer (2003)
Lajos Fodor Award: Ákos Sveiczer (2015)
Outstanding Educator of BME: Ákos Sveiczer (2017)
József Réffy Award: Ákos Sveiczer (2022)
Junior Prima Award – Hungarian Science Category: Judit Tóth (2010)
Certificate of Recognition – Ministry of Culture and Innovation: Ákos Sveiczer (2025)
Talentum Award: Judit Tóth (2012)
Pro Scientia Award: Judit Tóth (2012)
Gedeon Richter Doctoral Fellowship: Eszter Holub (2022–2026)
ÚNKP, EKÖP, DKÖP Fellowships: Kinga Nyíri (2016, 2020), Angéla Békési (2022–2024), Nikolett Emődi (2024), Milda Szajkó (2024; 2025–2026), Eszter Holub (2024), Judit Tóth (2018–2019)
KDP, NVKDP Fellowships:
András Telek (2021–2025), Nikolett Emődi (2024– )
Several OTKA Grants:
OTKA-PD (134324, …), OTKA-FK (137867, …), OTKA-K (…)

Key collaborations

International collaborations:

Hilde Nilsen – University of Oslo, Norway
Shailja Pathania – Boston University, USA
Grant Brown – University of Toronto, Canada
Melissa LaBonte Wilson – Queen’s University Belfast, UK
Edina Rosta – King’s College London, UK
Rachel Cerdan & Kai Wengelnik – University of Montpellier, France
Simak Ali – Imperial College London, UK
Martha S. Field – Cornell University, Ithaca, NY, USA

National Collaborations:

Máté Varga – Department of Genetics, Faculty of Sciences, ELTE, Budapest
Miklós Erdélyi – BRC, Szeged
László Acsády – HUN-REN Institute of Experimental Medicine (KOKI), Budapest
Gergely Róna – Institute of Molecular Life Sciences, HUN-REN Research Center for Natural Sciences, Budapest
Vince Grolmusz – Department of Computer Science, Faculty of Sciences, ELTE, Budapest
Gábor Tasnádi – Servier, Budapest
Béla Molnár – Semmelweis University, Department of Internal Medicine and Oncology & 3DHISTECH Ltd., Budapest
Sándor Spisák – HUN-REN TTK Institute of Molecular Life Sciences, Budapest
István Csabai – Faculty of Sciences, ELTE, Budapest
Mónika Molnár – BME VBK, Budapest
László Poppe – BME VBK, Budapest
András Perczel – Faculty of Sciences, ELTE, Budapest
Lajos Haracska – BRC, Szeged
Péter Burkovics – BRC, Szeged
Attila Patócs – National Institute of Oncology, Semmelweis University, Budapest
Levente Karaffa – University of Debrecen, Debrecen

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