Dawn S. Chandler, Ph.D.

Dawn S. Chandler, PhD is principal investigator in the Center for Childhood Cancer at The Research Institute at Nationwide Children’s Hospital and Associate Professor in the Department of Pediatrics at The Ohio State University College of Medicine. Dr. Chandler’s NIH funded research programs are focused on studying pre-mRNA splicing in the neurodegenerative disease, Spinal Muscular Atrophy(SMA), and in the pediatric cancer, rhabdomyosarcoma (RMS).

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Gender:

• Female

Languages Spoken:

• English

Research Center:

• Center for Childhood Cancer and Blood Diseases

Areas of Interest:

• Our lab is interested in the regulation of pre-mRNA splicing and how disruption of this regulation can lead to pediatric diseases such as cancer. Current work in our lab elucidates alternative splicing as a novel mechanism by which cellular injury can control the activity of p53 and how changes in the regulation of splicing can lead to tumorigenesis. The transcription factor p53 is known to induce G1 arrest of the cell cycle and/or apoptosis. MDM2 is one of the most critical regulators of p53. Using in vitro biochemical assays and genetically engineered mouse models we are currently investigating differential RNA splicing of both the MDM2 and p53 pre-mRNAs and investigating the roles of each in normal cell function as well as disease. Another pediatric disease Proximal Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality in humans, is in part due to a mutation that affects splicing of a duplicated gene that controls neuronal growth (SMN2). We are interested in generating viable mouse models for human SMA with the long-term goal of testing candidate therapies that target the human SMN2 gene. To do this, we are generating mouse lines that will be utilized to answer many questions pertaining the therapeutic possibilities of SMN replacement, splicing correction by drug or antisense treatment, and the correct timing of such therapies. Our research represents a novel perspective in pediatric research that highlights the role of perturbation of pre-mRNA processing in disease phenotypes. The increased awareness of regulated RNA processing and recent identification of several disease-causing mutations that affect splicing give rise to a new generation of potential therapeutic targets. Point mutations and the resultant splice variants may both be successfully targeted for therapeutic benefits in the future. Lab Website: http://www.nationwidechildrens.org/chandler-lab

Post Doctoral

• University of Texas Health Science Center
  Date Completed: 06/30/1998

Fellowship

• M.D. Anderson Cancer Center
  Date Completed: 06/30/2002

Fellowship

• M.D. Anderson Cancer Center
  Date Completed: 06/30/2004

• Bebee,Thomas,W; Dominguez,Catherine,E; Samadzadeh-Tarighat,Somayeh; Akehurst,Kristi,L; Chandler,Dawn,S. 2012. Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model.  HUMAN MOLECULAR GENETICS. Vol. 21, no. 19. (October): 4301-4313.
• Bebee,Thomas,W; Dominguez,Catherine,E; Chandler,Dawn,S. 2012. Mouse models of SMA: tools for disease characterization and therapeutic development.  HUMAN GENETICS. Vol. 131, no. 8. (August): 1277-1293.
• Pierson, C.R., Dulin-Smith, A.N., Durbin, A.N., Marshall, M.L., Marshall, J.T., Snyder, A.D., Naiyer, N., Gladman, J.T., Chandler, D.S., Lawlor, M.W., Buj-Bello, A., Dowling, J.J., Beggs, A.H. 2012. Modeling the human MTM1p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype.  Hum Mol Genet. Vol. 21, no. 4. (February): 811-825.
• O'Brien, D.O., Jacob, A.G., Qualman, S.J., Chandler, D.S. 2012. Advances in pediatric rhabdomyosarcoma characterization and disease model development.  Histol Histopathol. Vol. 27, no. 1. (January): 13-22.
• Bebee, T.W., Gladman, J.T., Chandler, D.S. 2011. Generation of a tamoxifen inducible SMN mouse for temporal SMN replacement.  Genesis. Vol. 49, no. 12. (December): 927-934.
• TW Beebe, DS Chandler (2011). Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing. In R Chuen-Chung Chang (Ed.) Advanced Understanding of Neurodegenerative Diseases. InTech. http://www.intechopen.com/articles/show/title/modeling-spinal-muscular-atrophy-in-mouse-a-disease-of-splicing-stability-and-timing
• Bebee, T.W., and Chandler, D.S. 2011. Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing. In Advanced Understanding of Neurodegenerative Diseases. Rijeka: InTech Publishers.
• Gladman, J.T., Bebee, T.W., Edwards, C., Wang, X., Sahenk, Z., Rich, M.M., and Chandler, D.S. 2010. A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.  Hum Mol Genet. Vol. 19, no. 21. (November): 4239-4252.
• Bebee, T.W., Gladman, J.T., and Chandler, D.S. 2010. Splicing regulation of the survival motor neuron genes and implications for treatment of spinal muscular atrophy.  Front Biosci. Vol. 15, no. June: 1191-1204.
• Gladman, J.T., Chandler, D.S. 2009. Splicing of the SMN gene is regulated by conserved elements located in intron 7.  Hum Genet. Vol. 126, no. 6. (December): 833-841.
• Singh, R.K., Tapia-Santos, A., Bebee, T.W., Chandler, D.S. 2009. Conserved sequences in the final intron of MDM2 are essential for the regulation of alternative splicing of MDM2 in response to stress.  Exp Cell Res. Vol. 315, no. 19. (November): 3419-3432.
• Lott, S.T., Chen, N., Chandler, D.S., Yang, Q., Wang, L., Rodriguez, M., Xie, H., Balasenthil, S., Buchholz, T.A., Sahin, A.A., Chaung, K., Zhang, B., Olufemi, S.E., Chen, J., Adams, H., Band, V., El-Naggar, A.K., Frazier, M.L., Keyomarsi, K., Hunt, K.K., Sen, S., Haffty, B., Hewitt, S.M., Krahe, R., Killary, A.M. 2009. DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.  PLoS Medicine. Vol. 6, no. 5. (May): ee1000068.
• Chandler, D.S. 2009. Alternative pre-mRNA Splicing in Cancer. In Encyclopedia of Cancer. Edited by Schwab, M.. New York, NY: Springer-Verlag.
• Jeyaraj, S., O'Brien, D.M., Chandler, D.S. 2009. MDM2 and MDM4 splicing: an integral part of the cancer spliceome.  Front Biosci. Vol. 14, no. January: 2647-2656.
• Wang, H., Garzon, R., Sun, H., Ladner, K.J., Singh, R., Dahlman, J., Cheng, A., Hall, B.M., Qualman, S.J., Chandler, D.S., Croce, C.M., Guttridge, D.C. 2008. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma.  Cancer Cell. Vol. 14, no. 5. (November): 369-381.
• Chandler, D.S. 2007. Regulation of p53 tumor suppressor activity by alternative splicing. In Alternative Splicing in Cancer. Edited by J.P. Venables. Kerala: Research Signpost Publishers.
• Chandler, D.S., Singh, R.K., Caldwell, L.C., Bitler, J.L., Lozano, G. 2006. Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4.  Cancer Res. Vol. 66, no. 19. (October): 9502-9508.
• Chandler, D.S. and Lozano, G. 2004. Metastasis. In Mouse Models of Human Cancer. Edited by E. Holland. New York, NY: John Wiley and Sons, Inc..
• Chandler, D.S., Qi, J., Mattox, W. 2003. Direct repression of splicing by transformer-2.  Mol Cell Biol. Vol. 23, no. 15. (August): 5174-5185.
• Lott, S.T., Chandler, D.S., Curley, S.A., Foster, C.J., El-Naggar, A., Frazier, M., Strong, L.C., Lovell, M., Killary, A.M. 2002. High frequency loss of heterozygosity in von Hippel-Lindau (VHL)-associated and sporadic pancreatic islet cell tumors: evidence for a stepwise mechanism for malignant conversion in VHL tumorigenesis.  Cancer Res. Vol. 62, no. 7. (April): 1952-1955.
• Chandler, D.S., McGuffin, M.E., Mattox, W. 2001. Functionally antagonistic sequences are required for normal autoregulation of Drosophila tra-2 pre-mRNA splicing.  Nucleic Acids Res. Vol. 29, no. 14. (July): 3012-3019.
• McGuffin, M.E., Chandler, D.S., Somaiya, D., Dauwalder, B. and Mattox, W. 1998. Autoregulation of transformer-2 alternative splicing is necessary for normal male fertility in Drosophila.  Genetics. Vol. 149, no. 3. (July): 1477-1486.
• Chandler, D., McGuffin, M.E., Piskur, J., Yao, J., Baker, B.S., Mattox, W. 1997. Evolutionary conservation of germline specific autoregulation by the sex determination factor transformer-2.  Mol Cell Biol. Vol. 17, no. 5. (May): 2908-2919.
• Pham, C.D., Runt, M., Chandler, D.S., Yang, Y., Arlinghaus, R.B., Rajagopalan, S., Schwartz, M.R., Singh, B. 1997. Essential role of c-Mos in eggs: reduced fertility and ovarian neoplasm in antisense mos transgenic mice.  International Journal of Gynecological Cancer. Vol. 7, no. January: 314-317.
• Chandler, D., El-Naggar, A.K., Brisbay, S., Redline, R.W., McDonnell, T.J. 1994. Apoptosis and expression of the bcl-2 proto-oncogene in the fetal and adult human kidney: Evidence for the contribution of bcl-2 expression to renal carcinogenesis.  Hum Pathol.. Vol. 25, no. 8. (August): 789-796.
• Bebee, T.W., Dominguez, C.E., Chandler, D.S. Mouse models of SMA: tools for disease characterization and therapeutic development.  Hum Genet.
• Bee T.W., Dominguez C.E., Samadzadeh-Tarighat S., Akehurst K.L., Chandler D.S. Hypoxia is a modifier of SMN2 s;icing and disease severity in a severe SMA mouse model.  Human Molecular Genetics.