5190 Biomedical Physical Science
Michigan State University
East Lansing MI 48823
Phone: (517) 884-5361
DNA is the blueprint for all living organisms; accordingly, all organisms have evolved numerous mechanisms to ensure maintenance of an exact copy of their genomes for propagation. Given its importance to life, it is somewhat surprising that evolution has allowed DNA to be so labile, being quite sensitive to various forms of damage including oxidation, hydrolysis and methylation. My laboratory studies how DNA double strand breaks (DSBs) are repaired.
Two major DNA repair pathways [non-homologous end joining (NHEJ) and homologous recombination (HR)] repair DSBs in all eukaryotes. NHEJ (the primary pathway in higher eukaryotes) is active throughout the cell cycle whereas HR is generally limited to S and G2 when a sister chromatid is available as a repair template. Emerging data provide strong evidence that an additional repair pathway(s) may also contribute to resolution of double strand breaks, especially in the absence of NHEJ, although the composition of this pathway as well as its role are not well understood.
My laboratory focuses on a large serine/threonine protein kinase: the DNA dependent protein kinase (DNA-PK). DNA-PK initiates NHEJ because it recognizes DNA ends and then targets other NHEJ factors to the site of damage. Emerging data implicate DNA-PK as a central regulator of DNA end access; ongoing studies are investigating how DNA-PK regulates DNA end access (primarily via autophosphorylation) to promote end joining with minimal loss of sequence information. Additionally, it is becoming apparent that DNA-PK may affect other repair pathways, potentially by limiting access of DNA ends to other repair factors. This may have particularly important sequelae in species that express very high levels of DNA-PK and may thus partially explain why DNA-PK may play varying roles in different species.
Ding, Q, Reddy, YVR., Wang, W, Woods, T, Douglas, P, Ramsden, DA, Lees-Miller, SP, and Meek. K. Autophosphorylation of the catalytic subunit of the DNA dependent protein kinase is required for efficient end processing during DNA double strand break repair. Mol. Cell. Biol. 23:5836-5848. 2003.
Meek, K, Gupta, S, Ramsden, DA, and Lees-Miller, SP. DNA-PK: Director at the End. Immunological Reviews. 2004 200:132-141.
Convery, E, Shin, EK, Ding, Q, Wang, W, Douglas, P, Davis, LS, Nickoloff, Lees-Miller, SP, Meek, K. Inhibition of homologous recombination by variants of DNA-PKcs. Proc. Natl. Acad Sci. USA. 102:1345-50 2005.
Cui, X, Yu, Y, Gupta, S, Cho, Y-M, Lees-Miller, SP, and Meek, K. Autophosphorylation of DNA-PK regulates DNA and processing and may also alter DSB repair pathway choice. Mol. Cell.Biol. 25:10842-10852. 2005.
Gupta, S, and Meek, K. The leucine rich region of DNA-PKcs contributes to its innate DNA affinity. Nucleic Acids Res. 33:6972-6981. 2005.
Douglas, P, Cui, X, Block, WD, Yu, T, Gupta, S, Ding, Q, Ye, R, Morrice, N, Lees-Miller, SP, and Meek, K. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol Cell Biol. 27:1581-1591. 2007.
Meek, K, Douglas, P, Cui, X, Ding, Q, and Lees-Miller, SP. Trans autophosphorylation at DNA-PK's two major autophosphorylation site clusters facilitates end processing but not end joining. Mol Cell Biol. 27:3881-3890. 2007.
Corneo, B, Wendland, R, Deriano, L, Cui, X, Klein, I, Wong, S, Arnal, S, Holub, AJ, Weller, GR, Pancake, BA, Shah, S, Brandt, VL, Meek, K, and Roth, DB. Rag mutations reveal robust alternative end joining. Nature 449:483-486. 2007.
Cui, X, and Meek, K. Linking DSBs to the RAG complex directs repair to the NHEJ pathway. Proc Natl Acad Sci. 104:17046-17051. 2007.
Meek, K, Dang, V, and Lees-Miller,S. DNA-PK: The means to justify the ends? Advances in Immunology, 99:33-58, 2008.
Meek, K, Jutkowitz, A, Allen, L, Glover, J, Convery, E, Massa, A, Mullaney, T, Stanley, B, Rosenstein, D, Johnson, C, Bailey, SM, Georges. G. SCID dogs: Similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence as compared to SCID mice. J. Immunol. 183:2529-2536. 2009.
Meek, K. New Targets to Translate DNA-PK Signals. Cell Cycle 8:3809. 2009.
Neal, JA, Dang, V, Douglas, P, Wold, MS, Lees-Miller, SP, Meek, K. Inhibition of HR by DNA-PK requires kinase activity, is titratable, and is modulated by autophosphorylation. Mol. Cell Biol. In press. 2011.
Neal, JA, Meek, K. Choosing the right path: does DNA-PK help make the decision? Mut. Res. in press. 2011.