---
_id: '10758'
abstract:
- lang: eng
  text: 5-Carboxycytosine (5caC) is a rare epigenetic modification found in nucleic
    acids of all domains of life. Despite its sparse genomic abundance, 5caC is presumed
    to play essential regulatory roles in transcription, maintenance and base-excision
    processes in DNA. In this work, we utilize nuclear magnetic resonance (NMR) spectroscopy
    to address the effects of 5caC incorporation into canonical DNA strands at multiple
    pH and temperature conditions. Our results demonstrate that 5caC has a pH-dependent
    global destabilizing and a base-pair mobility enhancing local impact on dsDNA,
    albeit without any detectable influence on the ground-state B-DNA structure. Measurement
    of hybridization thermodynamics and kinetics of 5caC-bearing DNA duplexes highlighted
    how acidic environment (pH 5.8 and 4.7) destabilizes the double-stranded structure
    by ∼10–20 kJ mol–1 at 37 °C when compared to the same sample at neutral pH. Protonation
    of 5caC results in a lower activation energy for the dissociation process and
    a higher barrier for annealing. Studies on conformational exchange on the microsecond
    time scale regime revealed a sharply localized base-pair motion involving exclusively
    the modified site and its immediate surroundings. By direct comparison with canonical
    and 5-formylcytosine (5fC)-edited strands, we were able to address the impact
    of the two most oxidized naturally occurring cytosine derivatives in the genome.
    These insights on 5caC’s subtle sensitivity to acidic pH contribute to the long-standing
    questions of its capacity as a substrate in base excision repair processes and
    its purpose as an independent, stable epigenetic mark.
acknowledgement: "We thank Markus Müller for valued discussions and Felix Xu for assistance
  in the measurement of UV/vis melting profiles. This work was supported in part by
  the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SFB 1309-325871075,
  EU-ITN LightDyNAmics (ID: 765266), the ERC-AG EpiR (ID: 741912), the Center for
  NanoScience, the Excellence Clusters CIPSM, and the Fonds der Chemischen Industrie.
  Open access funding provided by Institute of Science and Technology Austria (ISTA).\r\n\r\n"
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Romeo C. A.
  full_name: Dubini, Romeo C. A.
  last_name: Dubini
- first_name: Eva
  full_name: Korytiaková, Eva
  last_name: Korytiaková
- first_name: Thea
  full_name: Schinkel, Thea
  last_name: Schinkel
- first_name: Pia
  full_name: Heinrichs, Pia
  last_name: Heinrichs
- first_name: Thomas
  full_name: Carell, Thomas
  last_name: Carell
- first_name: Petra
  full_name: Rovo, Petra
  id: c316e53f-b965-11eb-b128-bb26acc59c00
  last_name: Rovo
  orcid: 0000-0001-8729-7326
citation:
  ama: Dubini RCA, Korytiaková E, Schinkel T, Heinrichs P, Carell T, Rovo P. 1H NMR
    chemical exchange techniques reveal local and global effects of oxidized cytosine
    derivatives. <i>ACS Physical Chemistry Au</i>. 2022;2(3):237-246. doi:<a href="https://doi.org/10.1021/acsphyschemau.1c00050">10.1021/acsphyschemau.1c00050</a>
  apa: Dubini, R. C. A., Korytiaková, E., Schinkel, T., Heinrichs, P., Carell, T.,
    &#38; Rovo, P. (2022). 1H NMR chemical exchange techniques reveal local and global
    effects of oxidized cytosine derivatives. <i>ACS Physical Chemistry Au</i>. American
    Chemical Society. <a href="https://doi.org/10.1021/acsphyschemau.1c00050">https://doi.org/10.1021/acsphyschemau.1c00050</a>
  chicago: Dubini, Romeo C. A., Eva Korytiaková, Thea Schinkel, Pia Heinrichs, Thomas
    Carell, and Petra Rovo. “1H NMR Chemical Exchange Techniques Reveal Local and
    Global Effects of Oxidized Cytosine Derivatives.” <i>ACS Physical Chemistry Au</i>.
    American Chemical Society, 2022. <a href="https://doi.org/10.1021/acsphyschemau.1c00050">https://doi.org/10.1021/acsphyschemau.1c00050</a>.
  ieee: R. C. A. Dubini, E. Korytiaková, T. Schinkel, P. Heinrichs, T. Carell, and
    P. Rovo, “1H NMR chemical exchange techniques reveal local and global effects
    of oxidized cytosine derivatives,” <i>ACS Physical Chemistry Au</i>, vol. 2, no.
    3. American Chemical Society, pp. 237–246, 2022.
  ista: Dubini RCA, Korytiaková E, Schinkel T, Heinrichs P, Carell T, Rovo P. 2022.
    1H NMR chemical exchange techniques reveal local and global effects of oxidized
    cytosine derivatives. ACS Physical Chemistry Au. 2(3), 237–246.
  mla: Dubini, Romeo C. A., et al. “1H NMR Chemical Exchange Techniques Reveal Local
    and Global Effects of Oxidized Cytosine Derivatives.” <i>ACS Physical Chemistry
    Au</i>, vol. 2, no. 3, American Chemical Society, 2022, pp. 237–46, doi:<a href="https://doi.org/10.1021/acsphyschemau.1c00050">10.1021/acsphyschemau.1c00050</a>.
  short: R.C.A. Dubini, E. Korytiaková, T. Schinkel, P. Heinrichs, T. Carell, P. Rovo,
    ACS Physical Chemistry Au 2 (2022) 237–246.
date_created: 2022-02-16T11:18:21Z
date_published: 2022-02-11T00:00:00Z
date_updated: 2023-01-31T07:33:07Z
day: '11'
ddc:
- '540'
department:
- _id: NMR
doi: 10.1021/acsphyschemau.1c00050
external_id:
  pmid:
  - '35637781'
file:
- access_level: open_access
  checksum: 5ce3f907848f5c7caf77f1adfe5826c6
  content_type: application/pdf
  creator: dernst
  date_created: 2022-07-29T07:53:20Z
  date_updated: 2022-07-29T07:53:20Z
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file_date_updated: 2022-07-29T07:53:20Z
has_accepted_license: '1'
intvolume: '         2'
issue: '3'
language:
- iso: eng
month: '02'
oa: 1
oa_version: Published Version
page: 237-246
pmid: 1
project:
- _id: B67AFEDC-15C9-11EA-A837-991A96BB2854
  name: IST Austria Open Access Fund
publication: ACS Physical Chemistry Au
publication_identifier:
  eissn:
  - 2694-2445
publication_status: published
publisher: American Chemical Society
quality_controlled: '1'
related_material:
  link:
  - relation: earlier_version
    url: https://www.biorxiv.org/content/10.1101/2021.12.14.472563
scopus_import: '1'
status: public
title: 1H NMR chemical exchange techniques reveal local and global effects of oxidized
  cytosine derivatives
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 2
year: '2022'
...
---
_id: '12228'
abstract:
- lang: eng
  text: The question of how RNA, as the principal carrier of genetic information evolved
    is fundamentally important for our understanding of the origin of life. The RNA
    molecule is far too complex to have formed in one evolutionary step, suggesting
    that ancestral proto-RNAs (first ancestor of RNA) may have existed, which evolved
    over time into the RNA of today. Here we show that isoxazole nucleosides, which
    are quickly formed from hydroxylamine, cyanoacetylene, urea and ribose, are plausible
    precursors for RNA. The isoxazole nucleoside can rearrange within an RNA-strand
    to give cytidine, which leads to an increase of pairing stability. If the proto-RNA
    contains a canonical seed-nucleoside with defined stereochemistry, the seed-nucleoside
    can control the configuration of the anomeric center that forms during the in-RNA
    transformation. The results demonstrate that RNA could have emerged from evolutionarily
    primitive precursor isoxazole ribosides after strand formation.
acknowledgement: We thank Stefan Wiedemann for the synthesis of reference compounds
  and Pia Heinrichs for assistance in the NMR measurements of the oligonucleotides.
  We also thank Dr. Luis Escobar and Jonas Feldmann for valued discussions. This work
  was supported by the German Research Foundation (DFG) for financial support via
  CRC1309 (Project ID 325871075, A04), CRC1361 (Project ID 893547839, P02) and CRC1032
  (Project ID 201269156, A5). This project has received funding from the European
  Research Council (ERC) under the European Union's Horizon 2020 research and innovation
  program under grant agreement No 741912 (EpiR). We are grateful for additional funding
  from the Volkswagen Foundation (EvoRib). Open Access funding enabled and organized
  by Projekt DEAL.
article_number: e202211945
article_processing_charge: No
article_type: original
author:
- first_name: Felix
  full_name: Xu, Felix
  last_name: Xu
- first_name: Antony
  full_name: Crisp, Antony
  last_name: Crisp
- first_name: Thea
  full_name: Schinkel, Thea
  last_name: Schinkel
- first_name: Romeo C. A.
  full_name: Dubini, Romeo C. A.
  last_name: Dubini
- first_name: Sarah
  full_name: Hübner, Sarah
  last_name: Hübner
- first_name: Sidney
  full_name: Becker, Sidney
  last_name: Becker
- first_name: Florian
  full_name: Schelter, Florian
  last_name: Schelter
- first_name: Petra
  full_name: Rovo, Petra
  id: c316e53f-b965-11eb-b128-bb26acc59c00
  last_name: Rovo
  orcid: 0000-0001-8729-7326
- first_name: Thomas
  full_name: Carell, Thomas
  last_name: Carell
citation:
  ama: Xu F, Crisp A, Schinkel T, et al. Isoxazole nucleosides as building blocks
    for a plausible proto‐RNA. <i>Angewandte Chemie International Edition</i>. 2022;61(45).
    doi:<a href="https://doi.org/10.1002/anie.202211945">10.1002/anie.202211945</a>
  apa: Xu, F., Crisp, A., Schinkel, T., Dubini, R. C. A., Hübner, S., Becker, S.,
    … Carell, T. (2022). Isoxazole nucleosides as building blocks for a plausible
    proto‐RNA. <i>Angewandte Chemie International Edition</i>. Wiley. <a href="https://doi.org/10.1002/anie.202211945">https://doi.org/10.1002/anie.202211945</a>
  chicago: Xu, Felix, Antony Crisp, Thea Schinkel, Romeo C. A. Dubini, Sarah Hübner,
    Sidney Becker, Florian Schelter, Petra Rovo, and Thomas Carell. “Isoxazole Nucleosides
    as Building Blocks for a Plausible Proto‐RNA.” <i>Angewandte Chemie International
    Edition</i>. Wiley, 2022. <a href="https://doi.org/10.1002/anie.202211945">https://doi.org/10.1002/anie.202211945</a>.
  ieee: F. Xu <i>et al.</i>, “Isoxazole nucleosides as building blocks for a plausible
    proto‐RNA,” <i>Angewandte Chemie International Edition</i>, vol. 61, no. 45. Wiley,
    2022.
  ista: Xu F, Crisp A, Schinkel T, Dubini RCA, Hübner S, Becker S, Schelter F, Rovo
    P, Carell T. 2022. Isoxazole nucleosides as building blocks for a plausible proto‐RNA.
    Angewandte Chemie International Edition. 61(45), e202211945.
  mla: Xu, Felix, et al. “Isoxazole Nucleosides as Building Blocks for a Plausible
    Proto‐RNA.” <i>Angewandte Chemie International Edition</i>, vol. 61, no. 45, e202211945,
    Wiley, 2022, doi:<a href="https://doi.org/10.1002/anie.202211945">10.1002/anie.202211945</a>.
  short: F. Xu, A. Crisp, T. Schinkel, R.C.A. Dubini, S. Hübner, S. Becker, F. Schelter,
    P. Rovo, T. Carell, Angewandte Chemie International Edition 61 (2022).
date_created: 2023-01-16T09:49:05Z
date_published: 2022-11-07T00:00:00Z
date_updated: 2023-08-04T09:32:42Z
day: '07'
ddc:
- '540'
department:
- _id: NMR
doi: 10.1002/anie.202211945
external_id:
  isi:
  - '000866428500001'
file:
- access_level: open_access
  checksum: 4e8152454d12025d13f6e6e9ca06b5d0
  content_type: application/pdf
  creator: dernst
  date_created: 2023-01-27T10:28:45Z
  date_updated: 2023-01-27T10:28:45Z
  file_id: '12422'
  file_name: 2022_AngewandteChemieInternat_Xu.pdf
  file_size: 1076715
  relation: main_file
  success: 1
file_date_updated: 2023-01-27T10:28:45Z
has_accepted_license: '1'
intvolume: '        61'
isi: 1
issue: '45'
keyword:
- General Chemistry
- Catalysis
language:
- iso: eng
month: '11'
oa: 1
oa_version: Published Version
publication: Angewandte Chemie International Edition
publication_identifier:
  eissn:
  - 1521-3773
  issn:
  - 1433-7851
publication_status: published
publisher: Wiley
quality_controlled: '1'
scopus_import: '1'
status: public
title: Isoxazole nucleosides as building blocks for a plausible proto‐RNA
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 61
year: '2022'
...