TY - JOUR AU - Lózsa, Rita Bernadett AU - Németh, Eszter AU - Gervai, Judit Zsuzsanna AU - Márkus, Bence Gábor AU - Kollarics, Sándor AU - Gyüre, Zsolt Tamás AU - Tóth, Judit AU - Simon, Ferenc AU - Szüts, Dávid TI - DNA mismatch repair protects the genome from oxygen-induced replicative mutagenesis JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - 20 SP - 11040 EP - 11055 PG - 16 SN - 0305-1048 DO - 10.1093/nar/gkad775 UR - https://m2.mtmt.hu/api/publication/34192915 ID - 34192915 AB - DNA mismatch repair (MMR) corrects mismatched DNA bases arising from multiple sources including polymerase errors and base damage. By detecting spontaneous mutagenesis using whole genome sequencing of cultured MMR deficient human cell lines, we show that a primary role of MMR is the repair of oxygen-induced mismatches. We found an approximately twofold higher mutation rate in MSH6 deficient DLD-1 cells or MHL1 deficient HCT116 cells exposed to atmospheric conditions as opposed to mild hypoxia, which correlated with oxidant levels measured using electron paramagnetic resonance spectroscopy. The oxygen-induced mutations were dominated by T to C base substitutions and single T deletions found primarily on the lagging strand. A broad sequence context preference, dependence on replication timing and a lack of transcriptional strand bias further suggested that oxygen-induced mutations arise from polymerase errors rather than oxidative base damage. We defined separate low and high oxygen-specific MMR deficiency mutation signatures common to the two cell lines and showed that the effect of oxygen is observable in MMR deficient cancer genomes, where it best correlates with the contribution of mutation signature SBS21. Our results imply that MMR corrects oxygen-induced genomic mismatches introduced by a replicative process in proliferating cells. Graphical Abstract LA - English DB - MTMT ER - TY - JOUR AU - Gyüre, Zsolt Tamás AU - Póti, Ádám AU - Németh, Eszter AU - Szikriszt, Bernadett AU - Lózsa, Rita Bernadett AU - Krawczyk, Michał AU - Richardson, Andrea L. AU - Szüts, Dávid TI - Spontaneous mutagenesis in human cells is controlled by REV1-Polymerase ζ and PRIMPOL JF - CELL REPORTS J2 - CELL REP VL - 42 PY - 2023 IS - 8 PG - 18 SN - 2211-1247 DO - 10.1016/j.celrep.2023.112887 UR - https://m2.mtmt.hu/api/publication/34083629 ID - 34083629 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Doctoral School of Molecular Medicine, Semmelweis University, Budapest, 1085, Hungary Turbine Simulated Cell Technologies, Budapest, 1027, Hungary Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States National Laboratory for Drug Research and Development, Budapest, 1117, Hungary Cited By :2 Export Date: 17 January 2024 Correspondence Address: Richardson, A.L.; Johns Hopkins University School of MedicineUnited States; email: aricha58@jhu.edu Correspondence Address: Szüts, D.; Institute of Enzymology, Hungary; email: szuts.david@ttk.hu LA - English DB - MTMT ER - TY - JOUR AU - Rachel, A. DeWeerd AU - Németh, Eszter AU - Póti, Ádám AU - Nataliya, Petryk AU - Chunlong, Chen AU - Olivier, Hyrien AU - Szüts, Dávid AU - Abby, Margaret Green TI - Prospectively-defined patterns of APOBEC3A mutagenesis are prevalent in human cancers JF - CELL REPORTS J2 - CELL REP VL - 38 PY - 2022 IS - 12 SN - 2211-1247 DO - 10.1016/j.celrep.2022.110555 UR - https://m2.mtmt.hu/api/publication/32730598 ID - 32730598 N1 - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Epigenetics & Cell Fate UMR7216, CNRS, University of Paris, 35 rue Hélène Brion, Paris, 75013, France Institut Curie, Université PSL, Sorbonne Université, CNRS UMR3244, Dynamics of Genetic Information, Paris, France Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, Université PSL, 46 rue d'Ulm, Paris, 75005, France Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States Export Date: 19 April 2022 Correspondence Address: Szüts, D.; Institute of Enzymology, Hungary; email: szuts.david@ttk.hu Correspondence Address: Green, A.M.; Department of Pediatrics, United States; email: abby.green@wustl.edu Funding details: K_134779, PD_134818, VEKOP-2.3.3-15-2017-00014 Funding details: National Institutes of Health, NIH, K08 CA212299 Funding details: U.S. Department of Defense, DOD, CA200867 Funding details: American Cancer Society, ACS Funding details: Cancer Research Foundation, CRF Funding details: Association pour la Recherche sur le Cancer, ARC Funding details: Children's Discovery Institute, CDI Funding details: Washington University School of Medicine in St. Louis, WUSM Funding details: Agence Nationale de la Recherche, ANR, 19-CE12-0016-02 Funding details: Fondation pour la Recherche Médicale, FRM, ANR-10-INBS-09, FRM DEI201512344404 Funding details: Ligue Contre le Cancer, 2010 BLAN 161501 Funding details: Centre National de la Recherche Scientifique, CNRS, 18CT014-00 Funding details: Institut National Du Cancer, INCa, PLBIO19-076 Funding text 1: The authors thank all members of the Green and Szüts labs for critical evaluation of experimental data and thoughtful review of the manuscript. We are thankful to colleagues and collaborators for experimental discussions and manuscript editing, especially Drs. Matthew Weitzman, Rahul Kohli, Sebastien Landry, Jeffrey Bednarski, and members of the Bednarski lab. We acknowledge the high-throughput sequencing facility of I2BC for its sequencing and bioinformatics expertise. BioRender was used to generate schematic figures and the graphical abstract. This work was supported by funding from the American Cancer Society (to A.M.G.), the Cancer Research Foundation (to A.M.G.), the National Institutes of Health ( K08 CA212299 to A.M.G.), the Department of Defense ( CA200867 to A.M.G.), the Children's Discovery Institute and the Washington University School of Medicine (to A.M.G.), and the National Research Development and Innovation Office of Hungary ( K_134779 and VEKOP-2.3.3-15-2017-00014 to D.S. and PD_134818 to E.N.). The C.-L.C. lab is supported by the YPI program of I. Curie, the ATIP-Avenir program from Centre National de la Recherche Scientifique and Plan Cancer ( N°18CT014-00 ), the Agence Nationale de la Recherche ( ReDeFINe 19-CE12-0016-02 ), and Institut National Du Cancer ( PLBIO19-076 ). The O.H. lab is supported by Ligue Nationale Contre le Cancer (Comité de Paris), Agence Nationale de la Recherche ( ANR 2010 BLAN 161501 ), Association pour la Recherche sur le Cancer , the Fondation pour la Recherche Médicale ( FRM DEI201512344404 ), and the France Génomique national infrastructure “Investissements d’Avenir” program managed by the ANR (ANR-10-INBS-09). LA - English DB - MTMT ER - TY - JOUR AU - Chen, Dan AU - Gervai, Judit Zsuzsanna AU - Póti, Ádám AU - Németh, Eszter AU - Szeltner, Zoltán AU - Szikriszt, Bernadett AU - Gyüre, Zsolt Tamás AU - Zámborszky, Judit AU - Ceccon, Marta AU - d’Adda di Fagagna, Fabrizio AU - Szállási, Zoltán AU - Richardson, Andrea L. AU - Szüts, Dávid TI - BRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1 JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 13 PY - 2022 IS - 1 PG - 13 SN - 2041-1723 DO - 10.1038/s41467-021-27872-7 UR - https://m2.mtmt.hu/api/publication/32586615 ID - 32586615 N1 - These authors contributed equally: Dan Chen, Judit Z. Gervai. LA - English DB - MTMT ER - TY - JOUR AU - Balogh, Ria Katalin AU - Németh, Eszter AU - Jones, Nykola C. AU - Hoffmann, Søren Vrønning AU - Jancsó, Attila AU - Gyurcsik, Béla TI - A study on the secondary structure of the metalloregulatory protein CueR: effect of pH, metal ions and DNA JF - EUROPEAN BIOPHYSICS JOURNAL J2 - EUR BIOPHYS J VL - 50 PY - 2021 IS - 3-4 SP - 491 EP - 500 PG - 10 SN - 0175-7571 DO - 10.1007/s00249-021-01539-z UR - https://m2.mtmt.hu/api/publication/31999867 ID - 31999867 N1 - Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary Institute of Enzymology, Genome Stability Research Group, Research Centre for Natural Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary ISA, Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, Aarhus C, 8000, Denmark Cited By :1 Export Date: 28 July 2021 CODEN: EBJOE Correspondence Address: Gyurcsik, B.; Department of Inorganic and Analytical Chemistry, Dóm tér 7, Hungary; email: gyurcsik@chem.u-szeged.hu Funding details: European Cooperation in Science and Technology, COST, CA15126, NTP-NFTÖ-18-B-0137 Funding details: Emberi Eroforrások Minisztériuma, EMMI Funding details: Debreceni Egyetem, DE Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, 730872, GINOP-2.3.2-15-2016-00038, K_16/120130 Funding text 1: Financial support from the Hungarian National Research, Development and Innovation Office (GINOP-2.3.2-15-2016-00038 and K_16/120130), from the CALIPSOplus (EU Framework Programme for Research and Innovation HORIZON 2020, grant no. 730872) and from the COST Action CA15126 ARBRE MOBIEU is gratefully acknowledged. R.K.B. got a fellowship within the frame of NFTÖ-18 (NTP-NFTÖ-18-B-0137) New National Excellence Program of the Ministry of Human Capacities. The authors thank to Ferenc Bartha for useful discussions on CpHMD simulations, and Peter Waaben Thulstrup for his useful pieces of advice during SRCD measurements. National Information Infrastructure Development (NIIF) Programme is acknowledged for providing the supercomputing infrastructure at University of Debrecen (Debrecen2 server). Funding text 2: Financial support from the Hungarian National Research, Development and Innovation Office (GINOP-2.3.2-15-2016-00038 and K_16/120130), from the CALIPSOplus (EU Framework Programme for Research and Innovation HORIZON 2020, grant no. 730872) and from the COST Action CA15126 ARBRE MOBIEU is gratefully acknowledged. R.K.B. got a fellowship within the frame of NFT?-18 (NTP-NFT?-18-B-0137) New National Excellence Program of the Ministry of Human Capacities. The authors thank to Ferenc Bartha for useful discussions on CpHMD simulations, and Peter Waaben Thulstrup for his useful pieces of?advice during SRCD measurements. National Information Infrastructure Development (NIIF) Programme is acknowledged for providing the supercomputing infrastructure at University of Debrecen (Debrecen2 server). LA - English DB - MTMT ER - TY - JOUR AU - Szikriszt, Bernadett AU - Póti, Ádám AU - Németh, Eszter AU - Kanu, Nnennaya AU - Swanton, Charles AU - Szüts, Dávid TI - A comparative analysis of the mutagenicity of platinum-containing chemotherapeutic agents reveals direct and indirect mutagenic mechanisms JF - MUTAGENESIS J2 - MUTAGENESIS VL - 36 PY - 2021 IS - 1 SP - 75 EP - 86 PG - 12 SN - 0267-8357 DO - 10.1093/mutage/geab005 UR - https://m2.mtmt.hu/api/publication/31888942 ID - 31888942 N1 - Institute of Enzymology, Research Centre for Natural SciencesBudapest, Hungary Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, United Kingdom Export Date: 8 June 2021 LA - English DB - MTMT ER - TY - JOUR AU - Németh, Eszter AU - Lovrics, Anna AU - Gervai, Judit Zsuzsanna AU - Seki, M. AU - Rospo, G. AU - Bardelli, A. AU - Szüts, Dávid TI - Two main mutational processes operate in the absence of DNA mismatch repair JF - DNA REPAIR J2 - DNA REPAIR VL - 89 PY - 2020 SN - 1568-7864 DO - 10.1016/j.dnarep.2020.102827 UR - https://m2.mtmt.hu/api/publication/31240665 ID - 31240665 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Department of Biochemistry, Tohoku Medical & Pharmaceutical University, Miyagi, 981-8558, Japan Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO 10060, Italy Department of Oncology, University of Turin, Candiolo, TO 10060, Italy Export Date: 13 March 2020 CODEN: DRNEA Correspondence Address: Szüts, D.; Research Centre for Natural Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.hu Funding details: 21091 Funding details: PD_124467, K_124881, FIEK_16-1-2016-0005 Funding details: Fondazione per la Ricerca Biomedica, FORB Funding details: 22795 Funding details: Ministero della Salute Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 21923 Funding text 1: This work was supported by the National Research, Development and Innovation Office of Hungary (FIEK_16-1-2016-0005 and K_124881 to DS, PD_124467 to AL). The research leading to these results has received funding from Fondazione AIRC under 5 per Mille 2018 - ID. 21091 program ? P.I. Bardelli Alberto, AIRC IG 2018 - ID. 21923 project - PI Bardelli Alberto; Progetto NET-2011-02352137 Ministero della Salute (AB); AIRC-CRUK-FC AECC Accelerator Award contract 22795 (AB); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014 e 2015 Ministero della Salute (AB); Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Department of Biochemistry, Tohoku Medical & Pharmaceutical University, Miyagi, 981-8558, Japan Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO 10060, Italy Department of Oncology, University of Turin, Candiolo, TO 10060, Italy Export Date: 8 April 2020 CODEN: DRNEA Correspondence Address: Szüts, D.; Research Centre for Natural Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.hu Chemicals/CAS: DNA mismatch repair protein MSH2, 153700-72-2; MutL protein homolog 1, 155577-96-1 Funding details: PD_124467, K_124881, FIEK_16-1-2016-0005 Funding text 1: This work was supported by the National Research, Development and Innovation Office of Hungary ( FIEK_16-1-2016-0005 and K_124881 to DS, PD_124467 to AL). The research leading to these results has received funding from Fondazione AIRC under 5 per Mille 2018 - ID. 21091 program – P.I. Bardelli Alberto, AIRC IG 2018 - ID. 21923 project - PI Bardelli Alberto; Progetto NET-2011-02352137 Ministero della Salute (AB); AIRC-CRUK-FC AECC Accelerator Award contract 22795 (AB); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014 e 2015 Ministero della Salute (AB); Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Department of Biochemistry, Tohoku Medical & Pharmaceutical University, Miyagi, 981-8558, Japan Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO 10060, Italy Department of Oncology, University of Turin, Candiolo, TO 10060, Italy Cited By :1 Export Date: 10 June 2020 CODEN: DRNEA Correspondence Address: Szüts, D.; Research Centre for Natural Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.hu Chemicals/CAS: DNA mismatch repair protein MSH2, 153700-72-2; MutL protein homolog 1, 155577-96-1 Funding details: PD_124467, K_124881, FIEK_16-1-2016-0005 Funding text 1: This work was supported by the National Research, Development and Innovation Office of Hungary ( FIEK_16-1-2016-0005 and K_124881 to DS, PD_124467 to AL). The research leading to these results has received funding from Fondazione AIRC under 5 per Mille 2018 - ID. 21091 program – P.I. Bardelli Alberto, AIRC IG 2018 - ID. 21923 project - PI Bardelli Alberto; Progetto NET-2011-02352137 Ministero della Salute (AB); AIRC-CRUK-FC AECC Accelerator Award contract 22795 (AB); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014 e 2015 Ministero della Salute (AB); AB - The analysis of tumour genome sequences has demonstrated high rates of base substitution mutagenesis upon the inactivation of DNA mismatch repair (MMR), and the resulting somatic mutations in MMR deficient tumours appear to significantly enhance the response to immune therapy. A handful of different algorithmically derived base substitution mutation signatures have been attributed to MMR deficiency in tumour somatic mutation datasets. In contrast, mutation data obtained from whole genome sequences of isogenic wild type and MMR deficient cell lines in this study, as well as from published sources, show a more uniform experimental mutation spectrum of MMR deficiency. In order to resolve this discrepancy, we reanalysed mutation data from MMR deficient tumour whole exome and whole genome sequences. We derived two base substitution signatures using non-negative matrix factorisation, which together adequately describe mutagenesis in all tumour and cell line samples. The two new signatures broadly resemble COSMIC signatures 6 and 20, but perform better than existing COSMIC signatures at identifying MMR deficient tumours in mutation signature deconstruction. We show that the contribution of the two identified signatures, one of which is dominated by C to T mutations at CpG sites, is biased by the different sequence composition of the exome and the whole genome. We further show that the identity of the inactivated MMR gene, the tissue type, the mutational burden or the patient's age does not influence the mutation spectrum, but that a tendency for a greater contribution by the CpG mutational process is observed in tumours as compared to cultured cells. Our analysis suggest that two separable mutational processes operate in the genomes of MMR deficient cells. © 2020 The Author(s) LA - English DB - MTMT ER - TY - JOUR AU - Kovacsics, Daniella AU - Brózik, Anna AU - Tihanyi, Borbála AU - Matula, Zsolt AU - Borsy, Adrienn AU - Mészáros, Nikolett AU - Szabó, Edit Zsuzsanna AU - Németh, Eszter AU - Fóthi, Ábel AU - Zámbó, Boglárka AU - Szüts, Dávid AU - Várady, György AU - Orbán, Tamás I. AU - Apáti, Ágota AU - Sarkadi, Balázs TI - Precision-engineered reporter cell lines reveal ABCG2 regulation in live lung cancer cells JF - BIOCHEMICAL PHARMACOLOGY J2 - BIOCHEMIC PHARMACOL VL - 175 PY - 2020 PG - 14 SN - 0006-2952 DO - 10.1016/j.bcp.2020.113865 UR - https://m2.mtmt.hu/api/publication/31240593 ID - 31240593 N1 - Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary South-Pest Hospital Centre, National Institute of Hematology and Infectious Diseases, Laboratory of Molecular and Cytogenetics, Budapest, Hungary Cited By :9 Export Date: 20 October 2022 CODEN: BCPCA Correspondence Address: Sarkadi, B.; Research Centre for Natural Sciences, Rm. D2.03A, Magyar tudósok körútja 2., Hungary; email: sarkadi.balazs@ttk.hu Chemicals/CAS: cisplatin, 15663-27-1, 26035-31-4, 96081-74-2; clemastine, 15686-51-8; cobalt chloride, 1332-82-7, 7646-79-9; colchicine, 64-86-8; dexamethasone, 50-02-2; docetaxel, 114977-28-5; etoposide, 33419-42-0, 433304-61-1; flavopiridol, 131740-09-5, 146426-40-6; gemcitabine, 103882-84-4; hydrocortisone, 50-23-7; methylprednisolone, 6923-42-8, 83-43-2; mitoxantrone, 65271-80-9, 70476-82-3; paclitaxel, 33069-62-4; sodium ion, 17341-25-2; valproic acid, 1069-66-5, 99-66-1; vinblastine, 865-21-4; vorinostat, 149647-78-9; epidermal growth factor receptor, 79079-06-4; ABCG2 protein, human; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; CRISPR-Associated Protein 9; EGFR protein, human; ErbB Receptors; Neoplasm Proteins AB - Expression of the ABCG2 multidrug transporter is a marker of cancer stem cells and a predictor of recurrent malignant disease. Understanding how human ABCG2 expression is modulated by pharmacotherapy is crucial in guiding therapeutic recommendations and may aid rational drug development. Genome edited reporter cells are useful in investigating gene regulation and visualizing protein activity in live cells but require precise targeting to preserve native regulatory regions. Here, we describe a fluorescent reporter assay that allows the noninvasive assessment of ABCG2 regulation in human lung adenocarcinoma cells. Using CRISPR-Cas9 gene editing coupled with homology-directed repair, we targeted an eGFP coding sequence to the translational start site of ABCG2, generating ABCG2 knock-out and in situ tagged ABCG2 reporter cells. Using the engineered cell lines, we show that ABCG2 is upregulated by a number of anti-cancer medications, HDAC inhibitors, hypoxia-mimicking agents and glucocorticoids, supporting a model in which ABCG2 is under the control of a general stress response. To our knowledge, this is the first description of a fluorescent reporter assay system designed to follow the endogenous regulation of a human ABC transporter in live cells. The information gained may guide therapy recommendations and aid rational drug design. LA - English DB - MTMT ER - TY - JOUR AU - Póti, Ádám AU - Gyergyák, Hella AU - Németh, Eszter AU - Rusz, Orsolya AU - Tóth, Szilárd AU - Kovácsházi, Csenger AU - Chen, Dan AU - Szikriszt, Bernadett AU - Spisák, Sándor AU - Takeda, Shunichi AU - Szakács, Gergely AU - Szállási, Zoltán AU - Richardson, Andrea L AU - Szüts, Dávid TI - Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. JF - GENOME BIOLOGY J2 - GENOME BIOL VL - 20 PY - 2019 IS - 1 PG - 13 SN - 1474-7596 DO - 10.1186/s13059-019-1867-0 UR - https://m2.mtmt.hu/api/publication/30923894 ID - 30923894 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Budapest, H-1117, Hungary Department of Oncotherapy, University of Szeged, Szeged, Hungary Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, United States Department of Radiation Genetics, Kyoto University Medical School, Kyoto, 606-8501, Japan Institute of Cancer Research, Medical University Vienna, Vienna, Austria Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, United States Harvard Medical School, Boston, MA, United States Danish Cancer Society Research Center, Copenhagen, Denmark SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Johns Hopkins University, School of Medicine, Baltimore, MD, United States Cited By :2 Export Date: 8 April 2020 CODEN: GNBLF Correspondence Address: Szüts, D.; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.mta.hu Chemicals/CAS: Poly(ADP-ribose) Polymerase Inhibitors Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Budapest, H-1117, Hungary Department of Oncotherapy, University of Szeged, Szeged, Hungary Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, United States Department of Radiation Genetics, Kyoto University Medical School, Kyoto, 606-8501, Japan Institute of Cancer Research, Medical University Vienna, Vienna, Austria Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, United States Harvard Medical School, Boston, MA, United States Danish Cancer Society Research Center, Copenhagen, Denmark SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Johns Hopkins University, School of Medicine, Baltimore, MD, United States Cited By :3 Export Date: 10 June 2020 CODEN: GNBLF Correspondence Address: Szüts, D.; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok krt 2, Hungary; email: szuts.david@ttk.mta.hu Chemicals/CAS: Poly(ADP-ribose) Polymerase Inhibitors AB - Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction.Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity.Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity. LA - English DB - MTMT ER - TY - JOUR AU - Németh, Eszter AU - Krzystanek, Marcin AU - Reiniger, Lilla AU - Ribli, Dezső AU - Pipek, Orsolya Anna AU - Sztupinszki, Zsófia AU - Glasz, Tibor AU - Csabai, István AU - Moldvay, Judit AU - Szállási, Zoltán AU - Szüts, Dávid TI - The genomic imprint of cancer therapies helps timing the formation of metastases JF - INTERNATIONAL JOURNAL OF CANCER J2 - INT J CANCER VL - 145 PY - 2019 IS - 3 SP - 694 EP - 704 PG - 11 SN - 0020-7136 DO - 10.1002/ijc.32159 UR - https://m2.mtmt.hu/api/publication/30417572 ID - 30417572 LA - English DB - MTMT ER -