Department of Molecular and Cellular Biology Faculty . Dr. Mark D. Baker

Office: SSC 4453
Ext: 54788
Lab: SSC 4401
Ext: 54711

mdbaker@uoguelph.ca

Education

B.Sc.- Laurentian
M.Sc. - Waterloo
Ph.D. - Waterloo

Research

Research in my laboratory is focussed on the study of homologous genetic recombination in mammalian cells. Procedures that we use to obtain answers to questions in these areas include techniques in recombinant DNA/molecular genetics, immunological and immunochemical techniques and techniques in somatic cell genetics.

Summary

Recombination is the process by which genetic information is exchanged between DNA duplexes. This process causes genomes to undergo structural alterations leading to changes in the linkage relationship between genes or groups of genes. Recombination is important for the assembly and expression of genes, the generation of genetic diversity and the repair of DNA damage. However, recombination can also generate DNA structures, which lead to the development of cancer and other diseases.

The three research goals of my laboratory are,
(i) to understand the molecular genetic mechanisms of recombination in mammalian cells,
(ii) to understand how defects in recombination contribute to tumorigenesis, and
(iii) to understand the nature of recombination hotspots.

We are presently researching questions pertaining to,
(i) the mechanism and frequency of recombination in mammalian cells,
(ii) the role of large palindromes in promoting recombination within and between mammalian chromosomes,
(iii) mammalian heteroduplex DNA formation and repair during recombination,
(iv) genetics of strand invasion and 3' end polymerization,
(v) how DNA sequences act to stimulate recombination (i.e., recombination hot-spots),
(vi) non-crossover mechanisms of homologous recombination,
(vii) the genetic control of recombination (investigation of the role of the Rad52 epistasis group of genes, and the Breast Cancer 2 tumor suppressor gene, BRCA2).

One way we study recombination is by introducing DNA into mammalian cells and then determining how it recombines with its endogenous chromosomal target locus. This mode of recombination is called gene targeting. Potentially, gene targeting is an effective form of human gene therapy. We also study recombination as it occurs both within and between mammalian chromosomes. The experimental systems that are in use in our laboratory are yielding information which contributes to our understanding of the recombination process at the molecular level, and its importance in normal and pathological states.

Our research is supported by operating grants from the Canadian Institutes of Health Research (CIHR), and the Natural Sciences and Engineering Research Council (NSERC) of Canada.

Selected Publications

Mundia, M.M., Desai, V., Magwood, A.C. and Baker, M.D. 2014. Nascent DNA synthesis during homologous recombination is synergistically promoted by the Rad51 recombinase and DNA homology. Genetics 197: 107-119.  

Magwood, A.C., Malysewich, M.J., Cealic, I., Mundia, M.M., Knapp, J. and Baker, M.D. 2013. Endogenous levels of Rad51 and Brca2 are required for homologous recombination and regulated by homeostatic re-balancing. DNA Repair 12: 1122-1133.

Magwood, A.C., Mundia, M.M. and Baker, M.D. 2012. High levels of wild-type BRCA2 suppress homologous recombination. J. Mol. Biol. 421: 38-53. 

Si W.,  Mundia, M.M., Magwood, A.C., Mark A. L., McCulloch R. M. and Baker, M.D. 2010.   A strand invasion 3' polymerization intermediate of mammalian homologous recombination. Genetics 185: 443-457.

Lee, S.A., Roques, C., Magwood, A.C., Masson, J.-Y. and Baker, M.D. 2009. Brca2 deficiency in homologous recombination and its recovery by wild-type Rad51 expression. DNA Repair 8: 170-181

Ruksc, A, Bell-Rogers, P.L., Smith, J.D. and Baker, M.D. 2008. Analysis of spontaneous gene conversion tracts within and between mammalian chromosomes. J. Mol. Biol. 377: 337-351

Lee, S.A., Parsa, J-Y., Martin, A. and Baker, M.D. 2007. Activation-induced cytidine deaminase induces DNA break repair events more frequently in the immunoglobulin switch region than other sites in the mammalian genome. Eur. J. Immunol. 37: 3529-3539.

Ruksc, A., Birmingham, E.C., and Baker, M.D. 2007. DNA repair and recombination responses in mouse cells expressing wildtype and mutant forms of Rad51. DNA Repair 6: 1876-1889.

Lee, S.A. and Baker, M.D. 2007. Analysis of DNA repair and recombination responses in mouse cells depleted for Brca2 by SiRNA. DNA Repair 6:809-817.

McCulloch, R.D. and Baker, M.D. 2006. Analysis of one-sided marker patterns resulting from mammalian gene targeting. Genetics 172: 1767-1781.

Raynard, S.J. and Baker, M.D. 2004. Cis-acting regulatory sequences promote high-frequency gene conversion between repeated sequences in mammalian cells. Nucleic Acids Res. 32: 5916-5927..

Birmingham, E.C., Lee, S.A., McCulloch, R.M., and Baker, M.D. 2004. Testing predictions of the double-strand break repair model relating to crossing over in mammalian cells. Genetics 168: 1539-1555.

Read, L.R., Raynard, S.J., Ruksc, A. and Baker, M.D. 2004. Gene repeat expansion and contraction by spontaneous intrachromosomal homologous recombination in mammalian cells. Nucleic Acids Res. 32: 1184-1196.

Baker, M.D. 2004. Gene targeting at the chromosomal immunoglobulin locus: a model system for the study of mammalian homologous recombination mechanisms. In: Methods in Molecular Biology, Volume 262, Genetic Recombination: Reviews and Protocols. A. S. Waldman (ed.). Humana Press, Totowa, NJ, pp.143-155.

McCulloch, R.M., Read, L.R. and Baker, M.D. 2003. Strand invasion and DNA synthesis from the two 3' ends of a double-strand break in mammalian cells. Genetics 163: 1439-1447.

Raynard, S., and Baker, M.D. 2002. Incorporation of large heterologies into heteroduplex DNA during double-strand-break repair in mouse cells. Genetics 162: 977-985.

Raynard, S., Read, L. R., and Baker, M.D. 2002. Evidence for the murine IgH : locus acting as a hotspot for intrachromosomal homologous recombination. J. Immunol.168: 2332-2339.

Baker, M.D. and Birmingham, E.C. 2001. Evidence for biased Holliday junction cleavage and mismatch repair directed by junction cuts during double-strand-break repair in mammalian cells. Mol. Cell. Biol. 21: 3425-3435.

Li, J. and Baker, M.D. 2001. The mechanism of mammalian gene replacement is consistent with the formation of long regions of heteroduplex DNA associated with two crossing-over events. Mol. Cell. Biol.21: 501-510.

Li, J. and Baker, M.D. 2000. Mechanisms involved in targeted gene replacement in mammalian cells. Genetics156: 809-821.

Li, J. and Baker, M.D. 2000. Formation and repair of heteroduplex DNA on both sides of the double-strand-break during mammalian gene targeting. J. Mol. Biol.295: 505-516.

Li, J. and Baker, M.D. 2000. Use of a small palindrome genetic marker to investigate mechanisms of double-strand-break repair in mammalian cells. Genetics154: 1281-1289.

Grad Students

Maureen Mundia (Ph.D.)

Lab Technicians

Alissa Magwood

http:/www.ncbi.nlm.nih.gov/disease/Cancer.html.

http:/www.sanger.ac.uk/Projects/C_elegans/

http://www.fruitfly.org/

http://www.ncbi.nlm.nih.gov/Sitemap/index.html#HumanGenome/

The University of Guelph

Department of Molecular and Cellular Biology

Canadian Institutes for Health Research (CIHR)

National Sciences and Engineering Research Council (NSERC)

National Cancer Institute of Canada (NCIC)

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