Dr. Matthew Whitby
University of Oxford

The mechanisms of genetic recombination and DNA repair in fission yeast

Homologous recombination is a key process in DNA metabolism. It is required for the accurate segregation of chromosomes at meiosis, promotes DNA replication and repair, and generates genetic diversity by rearranging genes within and between chromosomes. Defects in the normal pathways of recombination and repair are associated with increased sensitivity to radiation, chromosome instability, altered mutation rates and reduced viability. In humans, diseases with known defects in repair and recombination include Bloom’s Syndrome, Werner’s Syndrome and Ataxia-telangiectasia, that are variously characterised by features such as abnormal growth, immunological deficiency, neurological disorder, cancer predisposition, premature ageing and increased mortality.

Our research focuses on deciphering the molecular details of the mechanisms that control and catalyse homologous recombination in eukaryotes. Our principle model organism is the fission yeast Schizosaccharomyces pombe, which is particularly amenable to the interdisciplinary range of genetical, biochemical and cytological approaches that we use.

Possible projects for a MIRT Program student would be:

1. Screening a collection of mutants to identify genes that are important for resolving meiotic recombination intermediates as crossover or noncrossover recombinant products.
2. Purification of recombination proteins and reconstitution of recombination reactions in vitro.
3. Determining the effect of different types of replication fork damage on the frequency and type of recombination.

References:

Doe C.L., Dixon J., Osman F. and Whitby M.C. (2000) Partial suppression of the fission yeast rqh1- phenotype by expression of a bacterial Holliday junction resolvase. EMBO J. 19, 2751-2762.
Doe C.L., Ahn JS., Dixon J. and Whitby M.C. (2002) Mus81-Eme1 and Rqh1 involvement in processing stalled and collapsed replication forks. J. Biol. Chem., 277, 32753-32759.
Whitby M.C., Osman F. and Dixon J. (2003) Cleavage of model replication forks by fission yeast Mus81-Eme1 and budding yeast Mus81-Mms4. J. Biol. Chem., 278, 6928-6935.
Osman F., Dixon J., Doe C.L. and Whitby M.C. (2003) Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis. Mol. Cell 12, 761-774.