---
_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. ACS Physical Chemistry Au. 2022;2(3):237-246. doi:10.1021/acsphyschemau.1c00050
apa: Dubini, R. C. A., 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. American
Chemical Society. https://doi.org/10.1021/acsphyschemau.1c00050
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.” ACS Physical Chemistry Au.
American Chemical Society, 2022. https://doi.org/10.1021/acsphyschemau.1c00050.
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,” ACS Physical Chemistry Au, 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.” ACS Physical Chemistry
Au, vol. 2, no. 3, American Chemical Society, 2022, pp. 237–46, doi:10.1021/acsphyschemau.1c00050.
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
file_id: '11692'
file_name: 2022_ACSPhysChemAU_Dubini.pdf
file_size: 2351220
relation: main_file
success: 1
file_date_updated: 2022-07-29T07:53:20Z
has_accepted_license: '1'
intvolume: ' 2'
issue: '3'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
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. Angewandte Chemie International Edition. 2022;61(45).
doi:10.1002/anie.202211945
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. Angewandte Chemie International Edition. Wiley. https://doi.org/10.1002/anie.202211945
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.” Angewandte Chemie International
Edition. Wiley, 2022. https://doi.org/10.1002/anie.202211945.
ieee: F. Xu et al., “Isoxazole nucleosides as building blocks for a plausible
proto‐RNA,” Angewandte Chemie International Edition, 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.” Angewandte Chemie International Edition, vol. 61, no. 45, e202211945,
Wiley, 2022, doi:10.1002/anie.202211945.
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'
...