Periodic Reporting for period 1 - AttoDNA (AttoDNA: how electronic motions affect the photostability of the genomic material)
Reporting period: 2018-03-01 to 2020-02-29
The goal of AttoDNA is to understand from a molecular standpoint the origins of the intrinsic photostability displayed by the canonical DNA/RNA nucleobases, which comprise our genetic lexicon. Photostability has been recently recognised as one of the main properties thought to play a crucial role in the selection of the nucleobase monomers in prebiotic extreme UV exposure, by encoding the genome using the most suitable (photostable) building blocks as an elegant solution to aid in its photo-protective design and thus defend itself against the threat of photochemical damage. An in-depth knowledge of this outstanding property also provides a unique perspective on the events where these photo-protection mechanisms fail, namely the photo-damage instances. This has direct societal connotations as it comprises the early molecular events behind the formation of skin cancer melanoma, but is also essential to understand the subsequent repair mechanisms mediated by electron transfers as those put in place by enzymes and/or in specific non-invasive treatments like photodynamic therapies, the most widespread treatment for cancer.
The overall objective of the project is to find the basic physical principles shared by all DNA bases that explain this photostability, and in the long term uncover how this property modulates DNA damage and has thus an impact in mutation rates and related diseases. This overall goal is split in a series of more specific tasks, which are:
- The development of a methodology that allows us to compare the theoretical models proposed face-to-face with experimental evidence for its unambiguous validation
- The study of UV-light based processes in DNA/RNA nucleobases, particularly focusing for the first time in the very early events corresponding to the electronic motion prior to nuclear rearrangement
- The study of ionising radiation events in DNA/RNA systems, which were unfeasible experimentally until now but that have become possible thanks to the advent of high-energy radiation sources like x-ray free electron laser (XFEL) facilities
AttoDNA has concluded that very short timescales (where electron dynamics occur) may play a more important role than initially thought, and is currently exploring how this may have influenced canonical DNA bases to be chosen during evolution over structurally similar non-canonical analogues. This is being explored coupled with UV-light radiation, and has been more thoroughly assessed with VUV and higher energy regimes, which are readily measurable in XFEL facilities and that provide a unique tool to monitor ultrafast events at the electronic timescale.
The overall objective of the project is to find the basic physical principles shared by all DNA bases that explain this photostability, and in the long term uncover how this property modulates DNA damage and has thus an impact in mutation rates and related diseases. This overall goal is split in a series of more specific tasks, which are:
- The development of a methodology that allows us to compare the theoretical models proposed face-to-face with experimental evidence for its unambiguous validation
- The study of UV-light based processes in DNA/RNA nucleobases, particularly focusing for the first time in the very early events corresponding to the electronic motion prior to nuclear rearrangement
- The study of ionising radiation events in DNA/RNA systems, which were unfeasible experimentally until now but that have become possible thanks to the advent of high-energy radiation sources like x-ray free electron laser (XFEL) facilities
AttoDNA has concluded that very short timescales (where electron dynamics occur) may play a more important role than initially thought, and is currently exploring how this may have influenced canonical DNA bases to be chosen during evolution over structurally similar non-canonical analogues. This is being explored coupled with UV-light radiation, and has been more thoroughly assessed with VUV and higher energy regimes, which are readily measurable in XFEL facilities and that provide a unique tool to monitor ultrafast events at the electronic timescale.
The work carried out has focused mostly on studying the lesser known effects of photoionisation in DNA, and which relate to DNA exposure to high-energy ionising radiation. This has led to the publication of 2 articles in scientific journals, with additional studies following shortly. These articles have assessed for the first time the electronic excited state decay of the cationic states accessible upon VUV-light irradiation in all DNA/RNA nucleobases, their tautomers, as well as in relevant non-canonical bases like isocytosine and xanthine, extending the unified ultrafast decay mechanisms of the nucleobases in the singlet manifold for explaining their photostability to the doublet manifold.This allows narrowing down the specific divergences in behaviour between canonical and non-canonical bases upon UV and VUV light exposure, which may hold important connotations currently under study in order to understand why the canonical nucleobases were chosen to build our genetic code.
The results are relevant to understand the mechanisms triggered in DNA upon UV and VUV light exposure, and provide insight into photo-protection, which will be used to better understand the mechanisms triggered when these fail, i.e. generation of mutations, from a novel viewpoint. Uncovering and understanding the specific molecular processes behind the formation of these deleterious species, and their dependence with radiation wavelength and intensity which is largely unknown, holds the premise to impact the next generation of radiation and photodynamic therapies, the main tools currently available to tackle cancer.
Additionally several international scientific high-profile conferences featuring the main figures in the field were attended and 10 talks were given (2 of those being invited), in meeting ranging from the ACS Fall Meeting 2019 in San Diego to the 3rd Workshop on DNA damage in Valencia in 2019 (where I won the best talk prize) or 2019 UK-IT meeting in photochemistry. To further disseminate the results across different audiences I have recently opened a Twitter account where I post all news related to the project, including a conference recently organised for early-career scientists working in theoretical photochemistry and spectroscopy and that further enabled the dissemination of the results to an early-career audience. This helped enhance the impact of AttoDNA while showcasing the personal and professional training sides of the project, which has enabled the creation of a large European network in this particular field of study.
The results are relevant to understand the mechanisms triggered in DNA upon UV and VUV light exposure, and provide insight into photo-protection, which will be used to better understand the mechanisms triggered when these fail, i.e. generation of mutations, from a novel viewpoint. Uncovering and understanding the specific molecular processes behind the formation of these deleterious species, and their dependence with radiation wavelength and intensity which is largely unknown, holds the premise to impact the next generation of radiation and photodynamic therapies, the main tools currently available to tackle cancer.
Additionally several international scientific high-profile conferences featuring the main figures in the field were attended and 10 talks were given (2 of those being invited), in meeting ranging from the ACS Fall Meeting 2019 in San Diego to the 3rd Workshop on DNA damage in Valencia in 2019 (where I won the best talk prize) or 2019 UK-IT meeting in photochemistry. To further disseminate the results across different audiences I have recently opened a Twitter account where I post all news related to the project, including a conference recently organised for early-career scientists working in theoretical photochemistry and spectroscopy and that further enabled the dissemination of the results to an early-career audience. This helped enhance the impact of AttoDNA while showcasing the personal and professional training sides of the project, which has enabled the creation of a large European network in this particular field of study.
The project posed one of the first mechanisms to explain cationic deactivation in DNA/RNA nucleobases and predicts future results in XFELs in these systems alongside spectral signatures to monitor experimentally with table-top UV/Vis and IR experiments in laboratories worldwide. Amongst the most important findings are uncovering the precise energetic windows in which relatively long-living electronic coherences are triggered in DNA/RNA systems upon UV and particularly VUV light exposure, and whose importance I am currently analysing in terms of the subsequent nuclear motion. This stands as a potential way in which DNA/RNA might have secured its integrity upon high-energy VUV light exposure in prebiotic times prior to the formation of the ozone layer.
The specific impact of the project is yet to come as the coherent states formed by using certain VUV light sources may in principle allow to shape the photo-reaction by external means controlling nuclear motion by imprinting information in the initial electronic states formed. This links with the novel field of attochemistry, and predicts ways in which electron rearrangements forced by external stimuli (lasers) may be used to guide photoreactions.
The ability to control reactions externally completely reshapes the paradigm of photochemistry, as we move from being able to observe ultrafast reactions to shaping their outcome externally and thus controlling the photo-products formed, which has a vast range of applications within bio-mimetics, materials, imaging and other fields yet to discover. Exerting full control on photo-reactions will have immense impact in the way we understand the field and I believe it to be a central piece in the future of photochemistry, molecular physics and physical chemistry in general, as it unsets the limits as to what might be achieved upon light exposure. From here onwards I plan to use these novel concepts to tackle DNA mutations from a molecular standpoint, pinpointing damage and finding ways to use external stimuli to revert photo-reactions (mutations) and thus developing alternative ways to tackle growing healthcare concerns like skin cancer melanoma, the second most incident case of cancer in the UK to date.
The specific impact of the project is yet to come as the coherent states formed by using certain VUV light sources may in principle allow to shape the photo-reaction by external means controlling nuclear motion by imprinting information in the initial electronic states formed. This links with the novel field of attochemistry, and predicts ways in which electron rearrangements forced by external stimuli (lasers) may be used to guide photoreactions.
The ability to control reactions externally completely reshapes the paradigm of photochemistry, as we move from being able to observe ultrafast reactions to shaping their outcome externally and thus controlling the photo-products formed, which has a vast range of applications within bio-mimetics, materials, imaging and other fields yet to discover. Exerting full control on photo-reactions will have immense impact in the way we understand the field and I believe it to be a central piece in the future of photochemistry, molecular physics and physical chemistry in general, as it unsets the limits as to what might be achieved upon light exposure. From here onwards I plan to use these novel concepts to tackle DNA mutations from a molecular standpoint, pinpointing damage and finding ways to use external stimuli to revert photo-reactions (mutations) and thus developing alternative ways to tackle growing healthcare concerns like skin cancer melanoma, the second most incident case of cancer in the UK to date.