Nick Lakin
Maintenance of genome integrity and DNA repair
Co-workers: Hong-Yu Wang, Regina Teo, Anne-Marie Couto, Stella Lempidaki, Christine Borer
The genome is under continual assault from a variety of agents that cause DNA damage. As such, cells have evolved a specialised network of pathways known as the DNA damage response (DDR), that detect, signal and repair DNA damage. Defects in the DDR results in genome instability and increased mutagenesis, two conditions associated with cancer progression. Indeed, DNA repair pathways are often inactivated in malignant cells and defects in the DDR are the underlying cause of certain hereditary disorders associated increased cancer predisposition. Therefore, understanding the mechanistic basis of DNA repair will provide insights into the underlying cause of carcinogenesis.
DNA double strand breaks (DSBs) are a particularly toxic variety of DNA lesion. The focus of my research is to understand DSB repair at the molecular level with specific reference to how breaks are detected, processed and repaired. To achieve this we use a variety of molecular and biochemical approaches in the model organism Dictyostelium in addition to human cells. These studies will provide an increased understanding of how DNA repair is achieved and how defects in these pathways can cause a variety of disease states including cancer.
Publications
- Couto, C. A.-M., Wang, H.-Y., Green, J.C.A., Kiely, R., Siddaway, R., Borer, C., Pears. C.J. and Lakin, N.D. (2011). PARP regulates non-homologous end-joining through retention of Ku at double strand breaks. J. Cell Biol. 194:367-375.
- Hsu D.-W., Kiely, R., Couto, C. A.-M., Wang, H.-Y., Hudson, J.J.R., Borer, C., Pears, C.J. and Lakin, N.D. (2011). DNA double-strand break repair pathway choice in Dictyostelium. J. Cell Sci. 124:1655-1663.
- Medhurst, A.L., Warmerdam, D.O., Akerman, I., Verwayen, E.H., Kanaar, R., Smits, V.A.J. and Lakin, N.D. (2008). ATR and Rad17 collaborate in modulating Rad9 localisation at sites of DNA damage. J. Cell Sci. 121:3933-3940.
- Adams, K.E., Medhurst, A.L., Dart, D.A. and Lakin N.D. (2006). Recruitment of ATR to sites of ionising radiation induced DNA damage requires ATM and components of the MRN protein complex. Oncogene. 25:3894-3904.
- Hudson, J.J.R., Hsu, D.-W., Guo, K., Zhukovskaya, N., Liu, P.-H., Williams, J.G., Pears, C.J. and Lakin, N.D. (2005). DNA-PKcs-dependent signalling of DNA damage in Dictyostelium discoideum. Curr. Biol. 15:1880-1885.
More Publications...
Research Images
Figure 1: Detection and Signaling of DNA damage by the ATM and ATR kinases
DNA double strand breaks results in activation of ATM. ATM phosphorylates and regulates a number of different substrates including Chk2, a kinase that in turn phosphorylates substrates that initiate cell cycle arrest in response to DNA damage. In contrast to ATM, ATR becomes activated in response to a wide variety of DNA damage architectures including DNA double strand breaks, replication stress and base damage induced by UV. ATR phosphorylates and activates Chk1, which proceeds to phosphorylate substrates required for cell cycle checkpoint activation
Figure 2: ATR is recruited to sites of single stranded DNA formed in response to DNA damage
Staining of cells using immunofluorescence reveals that ATR (green) relocates to discrete nuclear foci following administration of ionising radiation. ATR co-localise with sites of single stranded DNA (red) formed as a result of processing DNA damage in order to facilitate signaling and DNA repair.
Figure 3: The life cycle of Dictyostelium discoideum
Under optimal growth conditions amoebae are single celled. However, on starvation amoebae aggregate and differentiate to form a multicellular fruiting body with two distinct cell types: stalk and spore cells. When favourable conditions return, these spores germinate to return to an amoeboid state
Contact: nicholas.lakin@bioch.ox.ac.uk
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome