While great progress has been made in researching the genes involved in the onset and progression of cancer, the advent of microarray analysis has shown there are still many important genes that remain unstudied. To achieve a complete understanding of tumorigenesis and obtain an inclusive list of potential druggable targets, we need to identify the functions of the unstudied genes. One such protein, Mettl11a, was shown to be under-expressed in breast cancer, glioblastoma, and leukemia and overexpressed in colon cancer. However, little was known about its function. I identified Mettl11a as the first mammalian N-terminal methyltransferase and have renamed it NRMT (N-terminal RCC1 methyltransferase). NRMT is a highly conserved, ubiquitously expressed nuclear methyltransferase that can mono-, di-, or trimethylate the N-termini of proteins containing its consensus sequence. I originally purified NRMT as the N-terminal methyltransferase for the Ran-GEF RCC1, but have also verified the tumor suppressor retinoblastoma protein (RB), the oncoprotein SET, and a variety of other proteins as substrates. In support of the microarray data, initial functional studies have shown loss of NRMT disrupts RCC1 binding to DNA and causes growth and mitotic defects often considered to contribute to cancer progression. The work in my lab is aimed at understanding the role of N-terminal methylation on protein and cellular function, and discovering how misregulation of NRMT, and consequently N-terminal methylation, can lead to cancer progression.
Lindsay Bonsignore, Postdoctoral Fellow
John Tooley, Postdoctoral Fellow
Jon Faughn, Graduate Student
Kaitlyn Wendland, Graduate Student
Bonsignore, L.A.Tooley, J.G., Van Hoose, P.M., Wang, E, Cheng, A., Cole, M.P., and Schaner Tooley, C.E. (2015). NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging. Mechanisms of ageing and development 146, 42-52.
Bonsignore L.A., Sergesketter Butler, J.A., Klinge, C.M., and Schaner Tooley, C.E. (2015) Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis. Oncotarget6 (14),12248-12263.
Tooley, J.G, and Schaner Tooley, C.E. (2014) New roles for old modifications: Emerging roles of N-terminal post-translational modifications is development and disease. Protein Science, 23,1641-1649.
Petkowski, J.J., Bonsignore, L.A., Tooley, J.G., Wilkey, D., Merchant, M.L., Macara, I.G., and Schaner Tooley, C.E. (2013) NRMT2 is an N-terminal monomethylase that primes for its homolog NRMT1. Biochemical Journal456, 453-462.
Petkowski, J. J., Schaner Tooley, C. E.*, Shumilin, I. A., Anderson, L., Balsbaugh, J.L., Shabanowitz, J., Hunt, D. F., Minor, W., and Macara, I.G. (2012). Substrate specificity of the mammalian N-terminal methyltransferase NRMT. Biochemistry 51, 5942-5950. * Corresponding author
Schaner Tooley, C. E., Petkowski, J., Muratore-Schroeder, T., Balsbaugh, J., Shabanowitz, J., Sabat, M., Minor, W., Hunt, D., and Macara, I.G. (2010). NRMT is an a-N-methyltransferase that methylates RCC1 and Retinoblastoma Protein. Nature466 (7310), 1125-1128.
(Commentaries in Cell, Nature Reviews Molecular Cell Biology, and Faculty of 1000 Biology)
Chen, T., Muratore, T. L., Schaner-Tooley, C. E., Shabanowitz, J., Hunt, D. F., and Macara, I. G. (2007). N-terminal alpha-methylation of RCC1 is necessary for stable chromatin association and normal mitosis. Nature Cell Biology9 (5), 596-603.
Schaner, C. E. and Kelly, W. G., Germline chromatin (January 24, 2006), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.73.1, http://www.wormbook.org.
Bean, C.J.*, Schaner, C.E.*, and Kelly, W.G. (2004). Meiotic Pairing and Imprinted X Chromatin Assembly in C. elegans. Nature Genetics36 (1),100-105. * Authors contributed equally to this work
Schaner, C.E., Deshpande, G., Schedl, P.D., and Kelly, W. G. (2003). A Conserved Chromatin Architecture Marks and Maintains the Restricted Germ Cell Lineage in Worms and Flies. Developmental Cell5 (5), 747-757.
Kelly, W.G., Schaner, C.E., Dernburg, A.F., Lee, M.H., Kim, S.K., Villeneuve, A.M., and Reinke, V. (2002). X-chromosome silencing in the germline of C. elegans.Development129, 479-492.