Kevin M. Culligan

Research Assistant Professor

Department of Biochemistry and Molecular Biology

Ph.D. Oregon State University, 2000

Research Overview:

Cellular DNA is continually altered by mutagenic agents from the environment (e.g. UV light, radiation etc.) and cellular metabolism (e.g. reactive oxygen). This DNA damage, and the resulting mutation, contributes to many interesting phenomena in biology– evolution*, antibiotic resistance in bacteria, toxicity, initiation of cancerous cells in animals, treatments for cancer, to name a few. My lab is focused on the mechanisms that protect genes and genomes from excess DNA damage and mutation, using the plant Arabidopsis thaliana as a model system. Because the types of damage to DNA are so diverse, it is not surprising that the mechanisms and molecular pathways that monitor and repair DNA damage are very complex. What may be surprising, however, is that DNA maintenance and repair pathways are very well conserved, from single-celled microorganisms (such as yeasts), to plants, to humans. In other words, yeast and plant genomes encode the same general DNA repair pathways that are present in humans. Therefore, organisms such as yeasts and plants are useful “model systems” for the study of DNA repair and genome maintenance.

Two general mechanisms that we are actively pursuing in the lab are the regulation of DNA repair pathways, and how cells monitor and regulate cell-cycle progression in response to DNA damage. When a cell incurs DNA damage, the cell must first recognize the type of damage, and then mount an appropriate response. This response is not simply just a decision of the type of repair pathway to activate (Non-homologous end joining versus recombinational repair, for example), but also involves activating so-called cell-cycle “checkpoints” if DNA damage persists, and in the case of animals often involves a cellular life or death decision termed apoptosis. Consequently, we are interested in identifying novel genes and pathways involved in the initial response to DNA damage in Arabidopsis thaliana to gain insights into how plant cells protect themselves from genomic stress, potentially leading to insights into animal DNA repair and maintenance.

The protein kinases ATR and ATM are known master regulators of both the DNA repair and cell-cycle checkpoint responses to DNA damage in mammalian cells. We have recently shown that ATR and ATM play conserved roles in plant cells: ATR controls cell-cycle checkpoint responses to both replication blocks and double-strand breaks (DSBs) while ATM controls a variety of responses to DSBs. Fortunately, atr and atm "knockout" mutants (and the double) are not lethal in plants, unlike most animals, allowing a more straightforward genetic approach. We are currently identifying downstream molecular players of ATR and ATM and how they interrelate. Some techniques that we are currently employing to identify and characterize these downstream genes are classical genetic screens, and microarray technologies. For more info about microarrays see: http://www.ncbi.nlm.nih.gov/About/primer/microarrays.html

Overall, our goal is to better understand the highly complex pathways involved in DNA repair and genome maintenance in Arabidopsis, and apply this knowledge to better improve crop species, and potentially aid in the understanding of these pathways in humans as it relates to disease and cancer biology.

* Does not apply to individuals residing in Kansas

Undergraduate Research:

If you are currently an undergraduate (preferably majoring in biological sciences) in good academic standing, and would like to gain some research experience, please contact me about research opportunities in my lab.

302 Rudman Hall
603-862-2430
Email: k.culligan@unh.edu

Figure showing a model for the molecular pathways involved in the DNA damage response. (borrowed from CalBioChem)

Publications:

Culligan K.M. and Britt A.B. (2008) Both ATM and ATR promote the efficient and accurate processing of programmed meiotic double-strand breaks. Plant J. 55, 629–638.

Culligan K.M., Robertson, C.E., Foreman, J., Doerner, P., and Britt A.B. (2006) ATR and ATM play distinct and additive roles in response to ionizing radiation. Plant J. 48, 947-961.

Britt A.B. and Culligan K.M. (2005) Maintenance of the plant genome under natural light. BMC Plant Biology 5 (Suppl 1):S7.

Friesner J.D., Liu B., Culligan K.M., Britt AB. (2005) Ionizing Radiation-dependent {gamma}-H2AX Focus Formation Requires Ataxia Telangiectasia Mutated and Ataxia Telangiectasia Mutated and Rad3-related. Mol Biol Cell. 16(5):2566-76.

Culligan K.M., Tissier A., and Britt A.B. (2004) ATR regulates a G2-phase cell-cycle checkpoint in Arabidopsis thaliana. Plant Cell 16(5):1091-104.

Wu S.Y., Culligan K.M., Lamers M., Hays J. (2003) Dissimilar mispair-recognition spectra of Arabidopsis DNA-mismatch-repair proteins MSH2*MSH6 (MutSalpha) and MSH2*MSH7 (MutSgamma). Nucleic Acids Research 31(20):6027-34.

Culligan K.M. and Hays J. (2000) Arabidopsis MutS homologs—AtMSH2, AtMSH3, AtMSH6, and a novel AtMSH7—form three distinct protein heterodimers with different specificities for mismatched DNA. Plant Cell 12(6):991-1002.

Culligan K. M., Meyer-Gauen G., Lyons-Weiler J. and Hays J. (2000) Evolutionary origin, diversification and specialization of eukaryotic MutS homolog mismatch repair proteins.
Nucleic Acids Research 28(2):463-71.

Culligan K.M. and Hays J. (1997) DNA mismatch repair in plants: An Arabidopsis thaliana gene that predicts a protein belonging to the MSH2 subfamily of eukaryotic MutS homologs.
Plant Physiology 115(2):833-9.

Li Hm, Culligan K.M., Dixon R.A., and Chory J. (1995) CUE1: A Mesophyll Cell-Specific Positive Regulator of Light-Controlled Gene Expression in Arabidopsis. Plant Cell 7: 1599-1610.