DNA damage repair

DNA-damage happens in our cells all the time due to numerous reasons here among exhibition to various kinds of radiation. To prevent cell death the damage of the DNA-strand is sought repaired before dangerous mutations happen.

The types of damage can be single and double strand breaks where chemical bonds are destroyed in the backbone of the DNA. The damage can also be formation of a pyrimidine dimer, base loss, base change or cross-linkage.

Ionising radiation damage repair

Because of the high energy in ionising radiation, it is the most dangerous type of radiation. The energy is sufficient high enough to break the chemical bonds in the backbone to produce single or double strand breaks. If these breaks are not repaired in due time, they can cause cell death.

The repair process is started by a signalling phase where the repair enzymes are recruited and guided to the breakage site. Different molecules are responsible for this, and for double strand breaks the signalling molecule is called Ataxia-telangiectasia mutated (ATM). When it finds the DNA-break it starts a protein kinase that is crucial for the cell’s survival. Not much is known about how ATM finds the DNA-break before cell death is inevitable, but a model based on the Monte Carlo method is sought after by considering the diffusion process both outside and within the nucleus.

The repair process itself is a complicated multi-step mechanism involving multiple enzymes and protein complexes. The different stages are modelled using Molecular Dynamics (MD) to gain a better understanding of the detailed process and timescales of repairing a broken chemical bond.

UV-damage repair

UV radiation is not a powerful as ionising radiation, and it will not make single or double strand breaks in the backbone of the DNA. Instead UV radiation can lead to the formation of a photoproduct between two adjacent pyrimidine rings in the DNA, which can lead to mutagenesis and cancer if not repaired. To avoid this, a specialised enzyme called as DNA photolyase could interact with the photo lesion and repair it. Important for the repair to happen is the binding of the DNA and the coenzyme Flavin adenine dinucleotide (FAD). Photolyase is structurally highly homologous to a protein called cryptochrome and both proteins are biological activated similar, namely through Flavin co-factor photoexcitation. However cryptochrome cannot repair UV-damaged DNA. We use MD to investigate the binding between photolyase and the UV-damaged DNA and between cryptochrome and the UV-damaged DNA to get insight into important factors that govern the binding of UV-damaged DNA and reveal why cryptochrome cannot have this functionality.

Recent Publications

Activation of the DNA-repair mechanism through NBS1 and MRE11 diffusion, Ida Friis, Ilia A. Solov'yov, PLoS Computational Biology, 14, e1006362, (2018)
On binding specificity of (6-4) photolyase to a T(6-4)T DNA photoproduct, Katrine Aalbæk Jepsen, Ilia A. Solov'yov, European Physical Journal D, 71, 155-165, (2017)
Molecular dynamics studies of DNA photolyase and cryptochromes binding to DNA with a (6-4) photolesion, Katrine Aalbæk Jepsen, Odense, Denmark, 1 — 44, Bachelor Thesis, University of Southern Denmark, (2016)