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p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich's Ataxia

R. Helma, P. Bažantová, M. Petr, M. Adámik, D. Renčiuk, V. Tichý, A. Pastuchová, Z. Soldánová, P. Pečinka, RP. Bowater, M. Fojta, M. Brázdová,

. 2019 ; 24 (11) : . [pub] 20190531

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc19044785

Grantová podpora
19-15168S Grantová Agentura České Republiky
16-01625S Grantová Agentura České Republiky
GJ17-19170Y Grantová Agentura České Republiky
313/2017/FAF IGA VFU Brno
314/2017/FAF IGA VFU Brno
RVO68081707 Akademie Věd České Republiky
692068 H2020-TWINN-2015, BISON project
CZ.1.05/2.1.00/19.0388 European Regional Development Fund
LO1208 European Regional Development Fund
CZ.02.1.01/0.0/0.0/15_003/0000477 European Regional Development Fund

Expansions of trinucleotide repeats (TNRs) are associated with genetic disorders such as Friedreich's ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. Sequence and structure-selective modes of DNA recognition are among the main attributes of p53 protein. The focus of this work was analysis of the p53 structure-selective recognition of TNRs associated with human neurodegenerative diseases. Here, we studied binding of full length p53 and several deletion variants to TNRs folded into DNA hairpins or loops. We demonstrate that p53 binds to all studied non-B DNA structures, with a preference for non-B DNA structures formed by pyrimidine (Py) rich strands. Using deletion mutants, we determined the C-terminal DNA binding domain of p53 to be crucial for recognition of such non-B DNA structures. We also observed that p53 in vitro prefers binding to the Py-rich strand over the purine (Pu) rich strand in non-B DNA substrates formed by sequence derived from the first intron of the frataxin gene. The binding of p53 to this region was confirmed using chromatin immunoprecipitation in human Friedreich's ataxia fibroblast and adenocarcinoma cells. Altogether these observations provide further evidence that p53 binds to TNRs' non-B DNA structures.

Citace poskytuje Crossref.org

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$a Helma, Robert $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. rhelma@ibp.cz. Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42 Brno, Czech Republic. rhelma@ibp.cz. $7 xx0312816
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$a Expansions of trinucleotide repeats (TNRs) are associated with genetic disorders such as Friedreich's ataxia. The tumor suppressor p53 is a central regulator of cell fate in response to different types of insults. Sequence and structure-selective modes of DNA recognition are among the main attributes of p53 protein. The focus of this work was analysis of the p53 structure-selective recognition of TNRs associated with human neurodegenerative diseases. Here, we studied binding of full length p53 and several deletion variants to TNRs folded into DNA hairpins or loops. We demonstrate that p53 binds to all studied non-B DNA structures, with a preference for non-B DNA structures formed by pyrimidine (Py) rich strands. Using deletion mutants, we determined the C-terminal DNA binding domain of p53 to be crucial for recognition of such non-B DNA structures. We also observed that p53 in vitro prefers binding to the Py-rich strand over the purine (Pu) rich strand in non-B DNA substrates formed by sequence derived from the first intron of the frataxin gene. The binding of p53 to this region was confirmed using chromatin immunoprecipitation in human Friedreich's ataxia fibroblast and adenocarcinoma cells. Altogether these observations provide further evidence that p53 binds to TNRs' non-B DNA structures.
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$a Bažantová, Pavla $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. pavla.bazantova@gmail.com. Faculty of Science, University of Ostrava, Chittussiho 10, 701 03 Ostrava, Czech Republic. pavla.bazantova@gmail.com.
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$a Petr, Marek $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. zhlavek@ibp.cz. Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42 Brno, Czech Republic. zhlavek@ibp.cz.
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$a Tichý, Vlastimil $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. vlastim.tichy@gmail.com.
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$a Pastuchová, Alena $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. 357864@mail.muni.cz.
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$a Soldánová, Zuzana $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. babkovazuzana@gmail.com. Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42 Brno, Czech Republic. babkovazuzana@gmail.com.
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$a Pečinka, Petr $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. Petr.Pecinka@osu.cz. Faculty of Science, University of Ostrava, Chittussiho 10, 701 03 Ostrava, Czech Republic. Petr.Pecinka@osu.cz.
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$a Bowater, Richard P $u School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK. R.Bowater@uea.ac.uk.
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$a Fojta, Miroslav $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. fojta@ibp.cz. Central European Institute of Technology, Masaryk University, Kamenice 753/5, CZ-62500 Brno, Czech Republic. fojta@ibp.cz.
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$a Brázdová, Marie $u Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Královopolská 135, 612 65 Brno, Czech Republic. maruska@ibp.cz. Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého 1/3, 612 42 Brno, Czech Republic. maruska@ibp.cz.
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