While DNA replication is very processive, the rate of progression along the template is not uniform. The replication fork can encounter barriers during the polymerization process leading either to stalling, pausing or termination.
Such barriers can be constituted by damaged bases, bound proteins, structures in the template or difficult template such as repetitive sequences. We are interested in the cellular processes that occur at such barriers. One of our main interests is trying to understand how at replication barriers bound proteins actively signals the pausing or termination of replication forks.
In fission yeast, we have shown that replication barriers are involved in a controlling the process of cellular differentiation. Here we have identified a true replication termination site called RTS1 and a replication pause site called MPS1. Interestingly, at the MPS1 site pausing leads to the introduction of a new type of genetic mark that is constituted by ribonucletides incorporated into the DNA.
These ribonucleotides act themselves as a barrier for the replication fork inducing a programmed recombination event that lead to a change in cell type. While ribonucleotide marks has yet been shown to be involved in cellular differentiation in other systems, it is highly likely that replication barriers have a more general role in gene regulation and chromosome biology.
Understanding the mechanism of replication stalling is also important for human health. Stalling of replication forks lead to genetic instability and is thought to be a major underlying cause of cancer. Also, many cancer drugs act by stalling replication forks, leading to checkpoint activation and apoptosis. Thus, our research is aimed towards identifying future cancer drug targets, and diagnostic markers.
DNA Replication Laboratory
CURRENT RESEARCH PROJECTS
Marie Curie Cancer Care Transitional Programme Grant, Funded by: Marie Curie Cancer Care,
Project Start Date:
01/10/2009
Project End Date:
30/09/2012
Steinacher.R, Osman.F, Dalgaard J.Z, Lorenz,A, Whitby, M.C(2012) 'The DNA helicase Pfh1 promotes fork merging at replication termination sites to ensure genome stability'
Genes and Development
(0890-9369)
Dalgaard, J. Z., Godfrey E. L. & McFarlane R. J.(2011) 'Eukaryotic Replication Barriers: Where, How and Why'
[article]
McFarlane R. J., Al-Zeer, K. & Dalgaard J.Z.(2011) 'Eukaryotic DNA replication and recombination: an intimate association'
[article]
Rhind, N., Chen, Z., Yassour, M., Thompson, D. A. , Haas B. J., Habib, N., Wapinski, I., Roy, S., Lin, M. F., Heiman, D. I., Young, S. K., Furuya, K., Guo, Y., Pidoux, A., Chen, H. M., Robbertse, B., Goldberg, J. M., Aoki, K., Bayne, E. H., Berlin, A. M., Desjardins, C. A., Dobbs, E., Dukaj, L., Fan, L., FitzGerald, M. G., French, C., Gujja, S., Hansen, K., Keifenheim, D., Levin, J. Z., Mosher, R. A., Müller, C. A., Pfiffner, J., Priest, M., Russ, C., Smialowska, A., Swoboda, P., Sykes, S.M., Vaughn, M., Vengrova, S., Yoder, R., Zeng, Q., Allshire, R., Baulcombe, D., Birren, B.W., Brown, W., Ekwall, K., Kellis, M., Leatherwood, J., Levin, H., Margalit, H., Martienssen, R., Nieduszynski, C. A., Spatafora, J. W., Friedman, N., Dalgaard, J.Z., Baumann, P., Niki, H., Regev, A., & Nusbaum, C.(2011) 'Comparative Functional Genomics of the Fission Yeats'
Science
(0036-8075)
[article]
Sayrac, S., et al.(2011) 'Identification of a novel type of spacer element required for imprinting in fission yeast'
PLoS Genetics
7
(3), (1553-7404)
[article]
