Professor Lorraine Symington Phone: 212-305-7753 Lab Phone: 212-305-7753 Fax: 212-305-1468 Email: lss5@cumc.columbia.edu Website: https://www.symingtonlab.com

Professor Lorraine Symington
Phone: 212-305-7753
Lab Phone: 212-305-7753
Fax: 212-305-1468
Email: lss5@cumc.columbia.edu
Website: https://www.symingtonlab.com

Lorraine S. Symington, Ph.D.

Harold S. Ginsberg Professor and Director of Graduate Studies of Microbiology & Immunology
Member, National Academy of Sciences
Member, American Academy of Arts & Sciences
Fellow, American Association for the Advancement of Science
Ph.D., University of Glasgow

Genetics and biochemistry of DNA recombination and repair in yeast

Research
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.

 

Selected Publications

  1. Gnügge, R., Reginato, G., Cejka, P. and Symington, L.S. (2023) Sequence and chromatin features guide DNA double-strand break resection initiation. Molecular Cell S1097-2765(23)00113-2. https://doi.org/10.1016/j.molcel.2023.02.010 [Advance online publication.]

  2. Marie, L. and Symington, L.S. (2022) Mechanism for inverted-repeat recombination induced by a replication fork barrier. Nature Communications 13: 32. https://doi.org/10.1038/s41467-021-27443-w

  3. Sanford, E.J., Comstock, W.J., Faça, V.M., Vega, S.C., Gnügge, R., Symington, L.S. and Smolka, M.B. (2021) Phosphoproteomics reveals a distinctive Mec1/ATR signaling response upon DNA end hyper-resection. EMBO J. 40: e104566. https://doi.org/10.15252/embj.2020104566

  4. Stivison, E.A., Young, K.J., and Symington, L.S. (2020) Interstitial telomere sequences disrupt break-induced replication and drive formation of ectopic telomeres. Nucleic Acids Res. 48: 12697-12710.

  5. Gnugge, R. and Symington, L.S. (2020) Efficient DNA double-strand break formation at single or multiple defined sites in the Saccharomyces cerevisiae genome. Nucleic Acids Res. 48: e115.

  6. Yu, T.Y., Garcia, V.E. and Symington, L.S. (2019) CDK and Mec1/Tel1-catalyzed phosphorylation of Sae2 regulate different responses to DNA damage. Nucleic Acids Res. 47: 11238-11249.

  7. Donnianni, R.A., Zhou, Z.X., Lujan, S.A., Al-Zain, A., Garcia, V., Glancy, E., Burkholder, A.B., Kunkel, T.A. and Symington L.S. (2019) DNA polymerase delta synthesizes both strands during break-induced replication. Mol. Cell 76: 371-381.e4.

  8. Oh, J., Lee, S.J., Rothstein, R. and Symington, L.S. (2018) Mre11 and Rad50-mediated DNA tethering is essential for replisome stability and suppression of gross chromosome rearrangements. Cell Reports 25: 1681-1692.

  9. Yu, T.-Y., Kimble, M.T. and Symington, L.S. (2018) Sae2 functions independently of Mre11 nuclease to prevent Rad9 accumulation at DSBs and attenuate DNA damage signaling. Proc. Natl. Acad. Sci. U.S.A. 115: E11961-E11969.

  10. Gnugge, R., Oh, J. and Symington, L.S. (2018) Processing of DNA double-strand breaks in yeast. Methods Enzymol. 600: 1-24.

  11. Gnugge, R. and Symington, L.S. (2017) Keeping it real: MRX-Sae2 clipping of natural substrates. Genes Dev. 31: 2311-2312.

  12. Ruff, P., Donnianni, R.A., Glancy, E., Oh, J. and Symington, L.S. (2016) RPA stabilization of single-stranded DNA is critical for break-induced replication. Cell Rep. 17: 3359-3368.

  13. Ciccia, A. and Symington, L.S. (2016) Stressing out about RAD52. Mol. Cell 64: 1017-1019.

  14. Symington, L.S. (2016) Mechanism and regulation of DNA end resection in eukaryotes. Crit. Rev. Biochem. Mol. Biol. 51: 195-212.

  15. Oh, J., Al-Zain, A., Cannavo, E., Cejka, P. and Symington, L.S. (2016) Xrs2 dependent and independent functions of the Mre11-Rad50 complex. Mol. Cell 64: 405-415.

  16. Deng, S.K., Yin, Y., Petes, T.D. and Symington, L.S. (2015) Mre11-Sae2 and RPA collaborate to prevent palindromic gene amplification. Mol. Cell 60: 500-508.

  17. Chen, H., Donnianni, R.A., Handa, N., Deng, S.K., Oh, J., Timashev, L.A., Kowalczykowski, S.C. and Symington, L.S. (2015) Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. Proc. Natl. Acad. Sci. U.S.A.112: E1880-1887.

  18. Deng, S.K., Chen, H. and Symington, L.S. (2015) Replication protein A prevents promiscuous annealing between short sequence homologies: Implications for genome integrity. Bioessays37: 305-313.

  19. Symington, L.S., Rothstein, R. and Lisby, M. (2014) Mechanisms and regulation of mitotic recombination in Saccharomyces cerevisiae. Genetics 198: 795-835.

  20. Symington, L.S. (2014) DNA repair: Making the cut. Nature 514: 39-40.

  21. Lee, A.H., Symington, L.S. and Fidock, D.A. (2014) DNA repair mechanisms and their biological roles in the malaria parasite Plasmodium falciparum. Microbiol Mol. Biol. Rev. 78: 469-486.

  22. Deng, S.K., Gibb, B., Almeida, M.J., Greene, E.C. and Symington, L.S. (2014) RPA antagonizes microhomology-mediated repair of DNA double-strand breaks. Nature Struct. Mol. Biol. 21: 405-412.

  23. Eissler, C.L., Mazon, G., Powers, B.L., Savinov, S.N., Symington, L.S. and Hall, M.C. (2014) The Cdk/Cdc14 module controls activation of the Yen1 Holliday junction resolvase to promote genome stability. Mol. Cell 54: 80-93.

  24. Stafa, A., Donnianni, R.A., Timashev, L.A., Lam, A.F. and Symington, L.S. (2014) Template switching during break-induced replication is promoted by the Mph1 helicase in Saccharomyces cerevisiae. Genetics 196: 1017-1028.

  25. Mazon, G. and Symington, L.S. (2013) Mph1 and Mus81-Mms4 prevent aberrant processing of mitotic recombination intermediates. Mol. Cell 52: 63-74.

  26. Donnianni, R.A. and Symington, L.S. (2013) Break-induced replication occurs by conservative DNA synthesis. Proc. Natl. Acad. Sci. U.S.A. 110: 13475-13480.

  27. Chen, H., Lisby, M. and Symington, L.S. (2013) RPA coordinates DNA end resection and prevents formation of DNA hairpins. Mol. Cell 50: 589-600.

  28. 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.

  29. Klein, H.L. and Symington, L.S. (2012) Sgs1-the maestro of recombination. Cell 149: 257-259.

  30. Symington, L.S. and Gautier, J. (2011) Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 45: 247-271.

  31. Mott, C. and Symington, L.S. (2011) RAD51-independent inverted-repeat recombination by a strand-annealing mechanism. DNA Repair 10: 408-415.

  32. Mimitou, E.P. and Symington, L.S. (2011) DNA end resection-unraveling the tail. DNA Repair10: 344-348.

  33. 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. Mol. Cell 40: 988-1000.

  34. Marrero, V.A. and Symington, L.S. (2010) Extensive DNA end processing by Exo1 and Sgs1 inhibits break-induced replication. PLoS Genetics 6: e1001007.

  35. 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.

  36. 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.

  37. 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.

  38. Mimitou, E.P. and Symington, L.S. (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455: 770-774.

  39. 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.

  40. Smith, C.E., Llorente, B and Symington, L.S. (2007) Template switching during break-induced replication. Nature 447: 102-105.