Education & Training:
University of Texas Health Science Center, Houston, TX, 1998 Ph.D. in Biomedical Sciences
M.D. Anderson Cancer Center, Houston, TX, 2002 Postdoctoral Fellow Human Genetics
M.D. Anderson Cancer Center, Houston, TX, 2004 Postdoctoral Fellow Cancer Genetics

Research 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.

Selected Publications:

• Dominguez CE, Cunningham D, Chandler DS. SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities. Human Genetics 2017 Sep;136(9):1173-1191. doi: 10.1007/s00439-017-1835-2. Epub 2017 Aug 29. PubMed PMID: 28852871

• Comiskey DF, Jacob AG, Sanford BL, Montes M, Goodwin AK, Steiner H, Matsa E, Tapia-Santos, AS, Bebee TW, Grieves J, La Perle K, Boyaka P, Chandler DS. A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo. Oncogene. 2018 Jan 4;37(1):95-106. doi: 10.1038/onc.2017.282. Epub 2017 Sep 11. PubMed PMID: 28892044.

• Comiskey DF Jr, Jacob AG, Singh RK, Tapia-Santos AS, Chandler DS. Splicing factor SRSF1 negatively regulates alternative splicing of MDM2 under damage. Nucleic Acids Res. 2015 Apr 6;PubMed PMID: 25845590.

• Jacob AG, Singh RK, Comiskey DF Jr, Rouhier MF, Mohammad F, Bebee TW, Chandler DS. Stress- induced alternative splice forms of MDM2 and MDMX modulate the p53-pathway in distinct ways. PLoS One. 2014;9(8):e104444. PubMed PMID: 25105592; PubMed Central PMCID: PMC4126728.

• Jacob AG, Singh RK, Mohammad F, Bebee TW, Chandler DS. The splicing factor FUBP1 is required for the efficient splicing of oncogene MDM2 pre-mRNA. J Biol Chem. 2014 Jun 20;289(25):17350-64. PubMed PMID: 24798327; PubMed Central PMCID: PMC4067169.

• Jacob AG, O’Brien D, Singh RK, Comiskey DF Jr, Littleton RM, Mohammad F, Gladman JT, Widmann MC, Jeyaraj SC, Bolinger C, Anderson JR, Barkauskas DA, Boris-Lawrie K, Chandler DS. Stress- induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma. Neoplasia. 2013 Sep;15(9):1049-63. PubMed PMID: 24027430; PubMed Central PMCID: PMC3769884.

• Balkhi MY, Iwenofu OH, Bakkar N, Ladner KJ, Chandler DS, Houghton PJ, London CA, Kraybill W, Perrotti D, Croce CM, Keller C, Guttridge DC. miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR. Sci Signal. 2013 Jul 30;6(286):ra63. PubMed PMID: 23901138; PubMed Central PMCID: PMC3885907.

• Chen N, Balasenthil S, Reuther J, Frayna A, Wang Y, Chandler DS, Abruzzo LV, Rashid A, Rodriguez J, Lozano G, Cao Y, Lokken E, Chen J, Frazier ML, Sahin AA, Wistuba II, Sen S, Lott ST, Killary AM. DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial- mesenchymal transition. Cancer Discov. 2013 Oct;3(10):1172-89. PubMed PMID: 23838884; PubMed Central PMCID: PMC4107927.

• Bebee, T.W., Dominguez, C.E., Samadzadeh-Tarighat, S. Akehurst, K.L., Chandler, D.S. Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model. Hum. Mol. Genet., 19:4301-13, 2012.

• Bebee, T.W., Dominguez, C.E., Chandler, D.S. Mouse models of SMA: tools for disease characterization and therapeutic development. Hum. Genet., 131: 1277-1293, 2012.

• Pierson, C.R., Dulin-Smith, A.N., Durban, 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. Modeling the Human MTM1p.R69C Mutation in Murine MTM1 Results in Exon 4 Skipping and a Less Severe Myotubular Myopathy Phenotype. Hum. Mol. Genet., 21:8110825, 2012.

• O’Brien, D.O., Jacob, A.G., Qualman, S.J., Chandler, D.S. Advances in pediatric rhabdomyosarcoma characterization and disease model development. Histology and Histopathology, 27:13-22, 2012.

• Jeyaraj S, O’Brien DM, Chandler DS, MDM2 and MDM4 splicing: an integral part of the cancer spliceome. Front Biosci. 14:2647-2656, Review, 2009.

My NCBI Link: http://www.ncbi.nlm.nih.gov/sites/myncbi/dawn.chandler.1/bibliography/44591543/public/?sort=date&direction= ascending