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H2020Individual fellowship2021–2023

HRRinDNAwithSSB · Unraveling nanosecond motions in nucleic acids with high-resolution relaxometry: how dynamic is nicked DNA?

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2021-09-01 → 2023-08-31
EU contribution
€184,708
Participants
1
Scheme
MSCA-IF

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Results in brief

Unraveling nanosecond motions in nucleic acids with high-resolution relaxometry: how dynamic is nicked DNA?

Nucleic acids are vital for cellular life and have been shown to have a variety of functions ranging from information storage and transmission to catalysis. Central to their activity are the structures and dynamics they undergo. Understanding these processes is vital for characterising diseased states and the development of new therapeutics for a wide range of conditions from cancer to viral infections. Typically, nucleic acids are structurally characterized using X-ray crystallography, Cryo-Electron Microscopy (Cryo-EM), and high-field Nuclear Magnetic Resonance (NMR). However, none of these approaches are suitable for studying nanosecond time-scale motions. To address this issue, we will introduce a new method called High Resolution Relaxometry (HRR) to characterise dynamics in nucleic acids and apply it to a DNA helix. We expect that this will be the first general approach to obtain both time-scales and amplitudes for motions in both RNAs and DNAs. In conjunction to this we will carry our long molecular dynamics simulations to interpret our low field relaxation rates and provide an atomistic picture.

Data: CORDIS, © European Union

Project objective

What role do conformational dynamics play in DNA function and repair? Structures of DNA show local dynamics, conformational flexibility of bases, and large conformational changes in the double helix, indicating easily accessible motions. Yet studying fast motions in nucleic acids is challenging. To address this we will introduce High Resolution Relaxometry (HRR) and apply it to study single strand breaks (SSBs) in DNA. Nucleic acids are often studied at atomic resolution with X-ray crystallography and high-field Nuclear Magnetic Resonance (NMR). Yet neither is suitable to study ns-motions. X-ray crystallography does not report on dynamics while using high-field NMR leads to high resonance frequencies so little ns time-scale information is present. This presents a challenge: how to characterise fast motions in nucleic acids? We will develop a new methodological approach, HRR, to probe ns-motions in DNA. HRR was developed by the host team to study ns-motions in proteins. We will adapt these methods to investigate motions in DNA. We will compare dynamics occurring in intact DNA, DNA with a SSB and SSB DNA with a missing base. Understanding the motions in each DNA construct will establish the effects that each type of DNA damage have on the motional properties of DNA. This will elucidate how each type of damage affects the base pair stacking and the motions occurring at the breakpoint. Understanding the flexibility induced by DNA damage will have a significant role in understanding DNA repair and how damaged DNA is recognised. The DNA repair protein, PARP-1, is a cancer-drug target and recognizes SSBs. Our final objective is to uncover the role of DNA motions in SSB recognition by PARP-1. In summary we will develop HRR as a new method to investigate ns-motions in DNA, providing a general approach to study ns-motions in nucleic acids at atomic resolution. We will discover the fundamental motions in DNA, how they are affected by SSBs and lead to recognition by PARP-1.

Original text from CORDIS.

Participants

  • ECOLE NORMALE SUPERIEURE · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union