Dr Howard LindsayLecturer in Biomedical Sciences & Year 1 Director
My main research interests are the mechanisms that maintain genome stability, in particular the cellular responses to DNA damage and DNA replication stress. Using Xenopus cell-free egg extracts as a model system, the primary aim of this work is a greater understanding of the way the various DNA damage response pathways are integrated with the cell cycle machinery and how failure of these pathways can contribute to the development and progression of cancer.
DNA is constantly subjected to damage by endogenous and exogenous factors. If the DNA is not repaired then mutations can be generated which if allowed to persist, can lead to the development of diseases such as cancer. In order to ensure genome integrity, cells have evolved complex surveillance mechanisms to protect the integrity of the genome.
DNA damage responses, detect damaged DNA or stalled DNA replication and can initiate a range of cellular responses such as cell cycle arrest, DNA repair, or if damage is too extensive, to eliminate the cell through apoptosis. The importance of these pathways in preventing the development of cancer is illustrated by the identication of numerous human diseases caused by mutations in genes involved in DNA repair and DNA checkpoint pathways. Many of these diseses are characterised by developmental and neurological abnormalities but significantly most confer a predisposition to the development of cancer. Therefore, an understanding of how these pathways operate and impinge on other cellular processes is vital if human diseases such as cancer and are to be understood and treated successfully. The importance of maintaining genome stability pathways is also illustrated by the fact that the the pathways involved have been conserved through evolution with a high degree of similarity between yeast and human proteins.
In our work we use a combination of model systems (Xenopus cell-free extracts, chicken DT40 cells as well as mammalian cell culture, to dissect these complex signaling pathways. The Xenopus system also provides the opportunity to analyse the regulation of these pathways during development. Our main focus has been concerned with the DNA checkpoint proteins, in particular the role of the XRad17/RFC, XRad9/Rad1/Hus1 and Atr/Atrip complexes in the DNA replication checkpoint. This work is continuing along with projects concerning the repair of double strand DNA breaks by non-homologous endjoining (NHEJ) and the involvement of chromatin modifying factors required for the initiation of DNA replication, the checkpoint response and the coordination of DNA repair
Director of Year 1 Lancaster MBChB
PBL Facilitator (Year 1 and Year 2)
Convenor of Special Study Modules (SSM)
Biomedical and Life Science Undegraduate Research projects
PhD Supervision Interests
Please contact me if you are interested in doing a PhD in the area of genome stability and DNA replication. Details of specific projects available in my research group can usually be found on FindaPhd.com. Applications for self-funded study can be made at any time.