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.
Cip29 is phosphorylated following activation of the DNA damage response in Xenopus egg extracts
Holden, J., Taylor, E.M., Lindsay, H.D. 17/07/2017 In: PLoS ONE. 12, 7, 20 p.
Molecular basis for PrimPol recruitment to replication forks by RPA
Guilliam, T.A., Brissett, N.C., Ehlinger, A., Keen, B.A., Kolesar, P., Taylor, E.M., Bailey, L., Lindsay, H.D., Chazin, W.J., Doherty, A.J. 23/05/2017 In: Nature Communications. 8, 14 p.
DNA replication stress and cancer: cause or cure?
Taylor, E.M., Lindsay, H.D. 01/2016 In: Future Oncology. 12, 2, p. 221-237. 17 p.
PrimPol bypasses UV photoproducts during chromosomal DNA replication
Bianchi, J., Rudd, S.G., Jozwiakowski, S.K., Bailey, L.J., Soura, V., Taylor, E., Stevanovic, I., Green, A.J., Stracker, T.H., Lindsay, H., Doherty, A.J. 21/11/2013 In: Molecular Cell. 52, 4, p. 566-573. 8 p.
Depletion of Uhrf1 inhibits chromosomal DNA replication in Xenopus egg extracts
Taylor, E., Bonsu-Dartnall, N., Price, J., Lindsay, H. 20/06/2013 In: Nucleic Acids Research. 41, 16, p. 7725-7737. 13 p.
The Mre11/Rad50/Nbs1 complex functions in resection-based DNA end joining in Xenopus laevis.
Taylor, E.M., Cecillon, S.M., Bonis, A., Chapman, J.R., Povirk, L.F., Lindsay, H.D. 01/2010 In: Nucleic Acids Research. 38, 2, p. 441-454. 14 p.
A direct requirement for Xmus101 in ATR-mediated phosphorylation of Claspin bound Chk1 during checkpoint signaling.
Yan, S., Lindsay, H.D., Michael, W.M. 04/2006 In: Journal of Cell Biology. 173, 2, p. 181-186. 6 p.
Delineating the position of rad4+/cut5+ within the DNA-structure checkpoint pathways in Schizosaccharomyces pombe.
Harris, S., Kemplen, C., Caspari, T., Chan, C., Lindsay, H.D., Poitelea, M., Carr, A.M., Price, C. 1/09/2003 In: Journal of Cell Science. 116, 17, p. 3519-3529. 11 p.
Molecular Characterization of the Schizosaccharomyces pombe nbs1+ Gene Involved in DNA Repair and Telomere Maintenance.
Ueno, M., Nakazaki, T., Akamatsu, Y., Watanabe, K., Tomita, K., Lindsay, H.D., Shinagawa, H., Iwasaki, H. 09/2003 In: Molecular and Cellular Biology. 23, 18, p. 6553-6563. 11 p.
XRad17 Is Required for the Activation of XChk1 But Not XCds1 during Checkpoint Signaling in Xenopus.
Jones, R.E., Chapman, J.R., Puligilla, C., Murray, J.M., Car, A.M., Ford, C.C., Lindsay, H.D. 2003 In: Molecular Biology of the Cell. 14, 9, p. 3898-3910. 13 p.
DNA replication is required for the checkpoint response to damaged DNA in Xenopus egg extracts.
Stokes, M.P., Van Hatten, R., Lindsay, H.D., Michael, W.M. 09/2002 In: Journal of Cell Biology. 158, 5, p. 863-872. 10 p.
Characterization of Schizosaccharomyces pombe Hus1: a PCNA-Related Protein That Associates with Rad1 and Rad9.
Caspari, T., Dahlen, M., Kanter-Smoler, G., Lindsay, H.D., Hofmann, K., Papadimitriou, K., Sunnerhagen, P., Carr, A.M. 02/2000 In: Molecular and Cellular Biology. 20, 4, p. 1254-1262. 9 p.
Rad18 Is Required for DNA Repair and Checkpoint Responses in Fission Yeast.
Verkade, H.M., Bugg, S.J., Lindsay, H.D., Carr, A.M., O'Connell, M.J. 09/1999 In: Molecular Biology of the Cell. 10, 9, p. 2905-2918. 14 p.
Analysis of Rad3 and Chk1 protein kinases defines different checkpoint responses.
Martinho, R.G., Lindsay, H.D., Flaggs, G., DeMaggio, A.J., Hoekstra, M.F., Carr, A.M., Bentley, N.J. 15/12/1998 In: EMBO Journal. 17, 24, p. 7239-7249. 11 p.
S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe.
Lindsay, H.D., Griffiths, D.J.F., Edwards, R.J., Christensen, P.U., Murray, J.M., Osman, F., Walworth, N., Carr, A.M. 1/02/1998 In: Genes and Development. 12, 3, p. 382-395. 14 p.
Post-translational activation of non-homologous DNA end-joining in Xenopus oocyte extracts.
Aoufouchi, S., Patrick, T., Lindsay, H.D., Shall, S., Ford, C.C. 07/1997 In: FEBS Journal. 247, 2, p. 518-525. 8 p.
Dissection of the cell cycle using cell-free extracts from Xenopus laevis
Ford, C., Lindsay, H. 3/04/1996 In: Advances in molecular and cell biology. Elsevier Science Ltd. p. 117-211. 95 p.
Calcium requirements during mitotic cdc2 kinase activation and cyclin degradation in Xenopus egg extracts.
Lindsay, H.D., Whitaker, M.J., Ford, C.C. 11/1995 In: Journal of Cell Science. 108, 11, p. 3557-3568. 12 p.