DNA replication laboratory

Jacob Z. Dalgaard PhD - Group Leader

Trevor Eydmann, BSc
Sonya Vengrova, PhD
Suha Sayrac, BSc

We have moved!

With immediate effect the DNA Replication Laboratory has moved to the University of Warwick.

Our new contact details are as follows:

Clinical Sciences Research Institute
Gibbet Hill Campus
University of Warwick
Coventry CV4 7AL

Tel: +44(0)247-615-1170 (Office) +44(0)247-612-8361 (Lab)
Email: J.Z.Dalgaard@warwick.ac.uk

We are studying the details of DNA replication using fission yeast as a model organism. The fission yeast Schizosaccharomyces pombe shares the basic machinery involved in DNA replication process with human cells, and is technically suitable as a model organism in the laboratory. The focus of our laboratory is cellular processes associated with stalled replication forks.

S. pombe has evolved a mechanism where three different polar replication barriers act in concert to establish a programmed pattern of cellular differentiation required for spore formation. Thus, using the power of this system, processes can be identified and studied in a way that would not be possible in any other system. The obtained information is important for understanding the events leading to formation of cancerous cells as well as treatment; stalled replication forks can lead to genetic instability, and many drugs used for cancer treatment act by stalling replication forks.

Our key discoveries include a novel checkpoint pathway, which ensures the coordination of the copying processes of the two DNA strands. In the absence of this pathway, long single-stranded regions are formed in one of the chromatids. We believe that this pathway will be a key target for the development of novel cancer drugs. Similarly, human mutations in the homologous factors could be the cause for genetic instability, underlying the development of cancer.

Another key discovery is the identification of a novel type of DNA modifications. The central dogma is that DNA is transcribed into RNA, which is then translated into proteins. However, we have shown that RNA can be incorporated into DNA in a specific manner, and that these RNA residues have a biological function. In S. pombe, such RNA residues play a key role in mediating a cell type change required for sporulation.

During differentiation and development of the human body multiple cell types have to be formed. In some cases, this involves stem cells that have the potential to divide in a fashion where one daughter cell differentiates into more specialized cell-type. It is very likely that this differentiation involves such RNA residues in the genome, which act to mark which of the two genome copies is segregated into the differentiated daughter cell and which is retained in the stem cell.

Selected references:

Vengrova, S. and Dalgaard, J. Z. (2009)
High-resolution mapping of points of site-specific replication stalling.
Methods Mol. Biol., 521: 215-227.

Dalgaard, J.Z., Eydmann, T., Koulinchenko, M., Sayrac, S., Vengrova, S. and Yamada-Inagawa, T. (2009)
Random and site-specific replication termination.
Methods Mol. Biol., 521: 35-53.

Inagawa, T., Yamada-Inagawa, T., Eydmann, T., Mian, S., Wang, T.S. and Dalgaard, J.Z. (2009)
Schizosaccharomyces pombe Rtf2 mediates site-specific replication termination by inhibiting replication restart.
Proc. Natl. Acad. Sci. USA, 106(19): 7927-7932.

Eydmann, T., Sommariva, E., Inagawa, T., Mian, S., Klar, A.J. and Dalgaard, J.Z. (2008)
Rtf1-mediated eukaryotic site-specific replication termination.
Genetics, 180(1): 27-39.

Yamada-Inagawa, T., Klar, A.J.S. and Dalgaard, J.Z.  (2007)
Schizosaccharomyces pombe switches mating type by the synthesis-dependent strand-annealing mechanism.
Genetics, 177: 255-265.

Vengrova, S. and Dalgaard, J.Z.  (2006)
The wild-type Schizosaccharoymces pombe mat1 imprint consists of two ribonucleotides.
EMBO Reports, 7: 59-65.

Vengrova, S. and Dalgaard, D.Z. (2005)
The Schizosaccharomyces pombe imprint - nick or ribonucleotide(s)?
Current Biology, 15: R326-327.

Torres-Rosell, J., Machin, F., Farmer, S. Jarmuz, A., Eydmann, T., Dalgaard, J.Z. and Aragón, L. (2005)
SMC5 and SMC6 genes are required for the segregation of repetitive chromosome regions.
Nature Cell Biol., 7: 412-419.

Sommariva, E., Pellny, T.K., Karahan, N., Kumar, S., Huberman, J.A. and Dalgaard, J.Z. (2005)
Schizosaccharomyces pombe Swi1, Swi3 and Hsk1 are components of a novel S-phase response pathway to alkylation damage.
Mol. Cell. Biol., 25: 2770-2784.

Dalgaard, J.Z. and Vengrova, S. (2004)
Selective gene expression in multigene families from yeast to mammals.
Science's STKE, Review 17: 1-10.

Vengrova, S. and Dalgaard, J.Z. (2004)
RNAse sensitive DNA modification(s) initiates S.pombe mating-type switching.
Genes & Development 18: 794-804.

Codlin, S and Dalgaard, J.Z. (2003)
Complex mechanism of site specific DNA replication termination in fission yeast.
EMBO J. 22: 3431-3440.

Varga-Weisz, P.D. and Dalgaard, J.Z. (2002)
A mark in the core: silence no more!
Molecular Cell 9: 1154-1156.

Vengrova, S., Codlin, S. and Dalgaard, J. (2002)
Molecules in Focus: RTS1 - an eukaryotic terminator of replication.
Int. J. Biochem. and Cell Biol. 34: 1031-1034.

Dalgaard, J.Z. and Klar, A.J.S. (2001)
A DNA replication-arrest site RTS1 regulates imprinting by determining the direction of replication at mat1 in S.pombe.
Genes & Development 15: 2060-2068.