Lorraine S. Symington, Ph.D.

Professor of Microbiology & Immunology
Ph.D., University of Glasgow

Genetics and biochemistry of DNA recombination and repair in yeast

The process of homologous recombination plays essential roles in the mitotic and meiotic cell cycles of most eukaryotic organisms. During meiosis, the programmed formation and processing of double strand breaks by homologous recombination is obligatory to establish the mechanical force between chromosome homologues essential for their segregation. The absence of homologous recombination in meiosis leads to random segregation of homologues at the first meiotic division and formation of aneuploid gametes (spores in yeast).

Meiotic recombination also contributes to genetic diversity by creating new linkage arrangements between genes, or parts of genes. In mitotic cells, double strand breaks form during S-phase by the convergence of replication forks with transient single-strand lesions. These breaks are repaired by homologous recombination to restore the collapsed replication fork. The absence of homologous recombination functions in vertebrates results in the accumulation of chromosome and chromatid breaks during S-phase triggering apoptosis and cell death.

The recent discovery that several human cancer prone syndromes, for example, Nijmegin Breakage Syndrome and A-TLD, are caused by defects in double-strand break repair has highlighted the importance of this pathway in maintaining genome integrity and cancer avoidance. The genes required for the repair of double-strand breaks by homologous recombination in eukaryotes are members of the RAD52 group and most were identified in yeast by the sensitivity of mutants to ionizing radiation. Mutations in the RAD52 group genes lead to defects in meiotic and/or mitotic recombination providing evidence for a link between double-strand break (DSB) repair and homologous recombination. Homologues of the RAD52 group of genes have been identified in many other eukaryotes, and in some cases in prokaryotes and archaea, indicating that the recombinational repair pathway is highly conserved.

The focus of research in my laboratory during the last decade has been to identify new genes involved in homologous recombination and further characterization of the RAD52 group genes using budding yeast as a model system.

Please see our laboratory website for more information about our research.

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1. Mazon, G., Lam, A.F., Ho, C.K., Kupiec, M. and Symington, L.S. (2012) The Rad1-Rad10 nuclease promotes chromosome translocations between dispersed repeats. Nature Struct. Mol. Biol. 9: 964-971.
2. Klein, H.L. and Symington, L.S. (2012) Sgs1-the maestro of recombination. Cell 149: 257-259.
3. Symington, L.S. and Gautier, J. (2011) Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 45: 247-271.
4. Mott, C. and Symington, L.S. (2011) RAD51-independent inverted-repeat recombination by a strand-annealing mechanism. DNA Repair 10: 408-415.
5. Mimitou, E.P. and Symington, L.S. (2011) DNA end resection-unraveling the tail. DNA Repair 10: 344-348.
6. Ho, C.K., Mazon, G., Lam, A.F. and Symington, L.S. (2010) Mus81 and Yen1 promote reciprocal exchange during mitotic recombination to maintain genome integrity in budding yeast. Molecular Cell 40: 988-1000.
7. Marrero, V.A. and Symington, L.S. (2010) Extensive DNA end processing by Exo1 and Sgs1 inhibits break-induced replication. PLoS Genetics 6: e1001007.
8. Mimitou, E.P. and Symington, L.S. (2010) Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO Journal 29: 3358-3369.
9. Smith, C.E., Lam, A.F. and Symington, L.S. (2009) Aberrant double-strand break repair resulting in half crossovers in mutants defective for Rad51 or the DNA polymerase δ complex. Mol. Cell. Biol. 29: 1432-1441.
10. Ho, C.K., Lam, A.F. and Symington, L.S. (2009) Identification of nucleases and phosphatases by direct biochemical screen of the Saccharomyces cerevisiae proteome. PloS ONE 4: e6993.
11. Fung, C.W., Mozlin, A.M. and Symington, L.S. (2009) Suppression of the double-strand break repair defect of the Saccharomyces cerevisiae rad57 mutant. Genetics 181: 1195-1206.
12. Mimitou, E.P. and Symington, L.S. (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455: 770-774.
13. Malik, P.S. and Symington, L.S. (2008) Rad51 gain-of-function mutants that exhibit high affinity DNA binding casue DNA damage sensitivity in the absence of Srs2. Nucleic Acids Res. 36: 6504-6510.
14. Mozlin, A.M., Fung, C.W. and Symington, L.S. (2008) Role of the Saccharomyces cerevisiae Rad51 paralogs in sister-chromatid recombination. Genetics 178: 113-126.
15. Smith, C.E., Llorente, B and Symington, L.S. (2007) Template switching during break-induced replication. Nature 447: 102-105.
16. Krogh, B.S., Llorente, B., Lam, A. and Symington, L.S. (2005) Mutations in Mre11 phosphoesterase motif I that impair Saccharomyces cerevisiae Mre11-Rad50-Xrs2 complex stability in addition to nuclease activity. Genetics 117: 1561-70.
17. Langston, L.D. and Symington, L.S. (2004) Gene targeting in yeast is initiated by two independent strand invasions. Proc. Natl. Acad. Sci. USA 101: 15392-15397.

Professor Lorraine Symington
Phone: 212-305-7753
Lab Phone: 212-305-7753
Fax: 212-305-1468
Email:  lss5@columbia.edu
Website: www.microbiology.columbia.edu/
symington