My research background was initially focused on investigating an important nuclear enzyme, poly(ADP-ribose) polymerase (PARP), and its interaction with DNA polymerase a during DNA replication. With a solid background in mammalian DNA replication and repair, and enzymology, I spearheaded the research, design, and implementation of a number of seminal studies on the diverse roles of PARP in differentiation, DNA replication, and apoptosis, and was a key player in several exciting studies in which we determined a pivotal role for PARP in the DNA replication complex, in the early stages of apoptosis, in the maintenance of genomic integrity, as well as in the regulation of gene expression. My current research interests revolve around the roles of specific genes in molecular mechanisms of apoptosis, a form of cellular suicide important in both normal development and a number of human diseases, as well as the practical aspects of modulating this process in the development of therapeutic approaches to cancer, autoimmune, and neurodegenerative diseases, such as Parkinson’s Disease. Abnormalities in apoptotic regulation have been shown to play a critical role in pathogenesis of these diseases.

Ongoing Research Projects:

1) UVB and HPV in epithelial carcinogenesis: We continue to define the molecular mechanisms for the alterations that accompany immortalization, regression as well as progression into invasive skin carcinomas (squamous cell carcinomas and melanomas), which appear to involve the differential expression of the Id transcriptional repressor proteins Id2 and Id3. These studies have potential for development of therapeutics for the treatment of epithelial malignancies.

2) We are currently investigating the role(s) of the Id1 transcriptional repressor protein in invasiveness and metastasis of human breast cancer cells.

3) Studies are also ongoing on mechanisms of apoptosis in wild-type and mutant synuclein-induced cell death of human dopaminergic neurons: roles of caspase induction, mitochondrial toxicity, oxidative stress, and PARP activation.

Selected Publications

Wang, T., Simbulan-Rosenthal CM, Smulson, M., Chock, P.B., and Yang, D. Polyubiquitylation of PARP-1 through ubiquitin K48 is modulated by activated DNA, NAD+, and dipeptides. J. Cell. Biochem. (2008)

Simbulan-Rosenthal, C. M., Ray, R., Benton, B., Soeda, E., Daher, A., Anderson, D., Smith, W. J., and Rosenthal, D. S. Calmodulin mediates sulfur mustard toxicity in human keratinocytes. Toxicology 227 , 21-35 (2006).

Simbulan-Rosenthal, C. M., Daher, A., Trabosh, V., Chen, W.C., Gerstel, D., Soeda, E., and Rosenthal, D. S. Id3 induces a caspase-3 and -9- dependent apoptosis and mediates UVB-sensitization of HPV16 E6/7 immortalized human keratinocytes. Oncogene 25:3649-3660. (2006).

Simbulan-Rosenthal, C. M., Trabosh, V., Velarde, A., Chou, F., Daher, A., Tenzin, F., Tokino, T., and Rosenthal, D. S. Id2 protein is selectively upregulated by UVB in primary, but not in immortalized human keratinocytes and inhibits differentiation. Oncogene 24, 5443-5458 (2005).

Simbulan-Rosenthal, C. M., Rosenthal, D. S., Luo, R., Samara, S., Espinoza, L., Hassa, P., Hottiger, M., and Smulson, M.E. PARP-1 binds E2F-1 independently of its DNA-binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during reentry of quiescent cells into S-phase. Oncogene 22, 8460-8471 (2003).

Rosenthal, D. S., Velena, A., Chou, P., Schlegel, R., Ray, R., Benton, B., Anderson, D., Smith, W., and Simbulan-Rosenthal, C. M. Expression of dominant-negative Fas-associated death domain blocks human keratinocyte apoptosis and vesication induced by sulfur mustard. J. Biol. Chem. 278, 8531-8540 (2003).

Simbulan-Rosenthal, C. M., Velena, A., Veldman, T., Schlegel, R., and Rosenthal, D. S. HPV E6/7 immortalization sensitizes human keratinocytes to UVB by altering the pathway from caspase-8 to caspase-9-dependent apoptosis. J. Biol. Chem. 277, 24709-24716 (2002).

Simbulan-Rosenthal, C. M., Rosenthal, D. S., Luo, R., Samara, R., Jung, M., Dritschilo, A., Spoonde, A., and Smulson, M. E. Poly(ADP-ribosyl)ation of p53 in vitro and in vivo modulates binding to its DNA consensus sequence. Neoplasia 3, 179-188 (2001).

Simbulan-Rosenthal, C. M., Rosenthal, D. S., Luo, R., Li, J-H., Zhang, J., and Smulson, M. E. Inhibition of poly(ADP-ribose) polymerase activity is insufficient to induce tetraploidy. Nucleic Acids Res. 29, 841-849 (2001).

Simbulan-Rosenthal, C. M., Ly, D.H., Rosenthal, D. S., Konopka, G., Luo, R., Wang, Z.Q., Schultz, P., and Smulson, M. E. Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase. Proc. Natl. Acad. Sci. USA 97, 11274-11279 (2000).

Simbulan-Rosenthal, C. M., Haddad, B. R., Rosenthal, D. S., Weaver, Z., Coleman, A., Luo, R., Young, H., Wang, Z.Q., Ried, T., and Smulson, M. E. Chromosomal aberrations in PARP-/- mice: genome stabilization in immortalized cells by reintroduction of PARP cDNA. Proc. Natl. Acad. Sci. USA 96: 13191-13196 (1999).

Simbulan-Rosenthal, C. M., Rosenthal, D.S., Luo R., and Smulson, M. E. Poly(ADP-ribosyl)ation of p53 during apoptosis in human osteosarcoma cells. Cancer Res., 59, 2190-2194 (1999)

Simbulan-Rosenthal, C. M., Rosenthal, D.S., Luo, R., and Smulson, M. E. Poly(ADP-ribose) polymerase upregulates E2F-1 promoter activity and DNA pol a expression during entry into S-phase. Oncogene 18, 5015-5023 (1999)

Simbulan-Rosenthal, C. M., Rosenthal, D.S., Iyer, S., Boulares, H., and Smulson, M. E. Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication. Mol. Cell. Biochem. 193, 137-148 (1999)

Mandir, A.S., Przedborski, S., Jackson-Lewis, V., Wang, Z.Q., Simbulan-Rosenthal, C.M., Smulson, M.E., Hoffman, B.E., Guastella, D., Dawson, V.L., Dawson, T.M. Poly(ADP-ribosyl)ation activation mediates MPTP-induced Parkinsonism. Proc. Natl. Acad. Sci. USA, 96, 5774-5779 (1999)

Simbulan-Rosenthal, C. M., Rosenthal, D. S, Iyer, S., Boulares, H., and Smulson, M. E. Involvement of PARP and poly(ADP-ribosyl)ation in apoptosis and DNA replication. Mol. Cell. Biochem 193, 137-148 (1999).

Simbulan-Rosenthal, C. M., Rosenthal, D.S., Ding, R., Bhatia, K., and Smulson, M. E. Prolongation of the p53 response to DNA strand breaks in cells depleted of PARP by antisense RNA expression. Biochem. Biophys. Res. Commun., 253(3), 864-868 (1998).

Simbulan-Rosenthal, C. M., Rosenthal, D. S., Iyer, S., Boulares, A.H., and Smulson, M. E. Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis. J. Biol. Chem. 273(22), 13703-13712 (1998).

Simbulan-Rosenthal, C. M., Rosenthal, D. S., Boulares, A.H., Hickey, R., Malkas, L., Coll, J., and Smulson, M. E. Regulation of the expression or recruitment of components of the DNA synthesome by poly(ADP-ribose) polymerase. Biochemistry 37(26): 9363-9370 (1998).

Simbulan-Rosenthal, C. M. G., Rosenthal, D. S., Hilz, H., Hickey, R., Malkas, L., Applegren, N., Wu, Y., Bers, G., and Smulson, M. E. The expression of poly(ADP-ribose) polymerase during differentiation-linked DNA replication reveals that this enzyme is a component of the multiprotein DNA replication complex. Biochemistry.35(36):11622-11633 (1996)