Dr. Phillip B. Carpenter
The University of Texas Health Science Center at Houston
Department of Biochemistry and Molecular Biology
- DNA damage response and genomic stability: Models for lymphoma and other cancer
Our lab has been traditionally interested in the cellular response to DNA damage and more recently interested in the understanding the role of the nuclear receptor SET domain containing family, or "NSD" family in biological pathways that are relevant for health and disease. NSD proteins are very clinically relevant and have been found to be perturbed in numerous diseases including neuroblastoma, glioma, breast, multiple myeloma, and prostate cancer. In fact, a recent, epigenetic gene expression profiling study identified a candidate gene signature that includes NSD1 (DNMT3A, MBD4,MLL2, MLL3, NSD1, and SRCAP), that can significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. Translocations in NSD1 are well established to be causal for the generation of acute myeloid leukemia and overexpression of NSD2 has been implicated in multiple myeloma. Moreover, haploinsufficiency in NSD1 is the major, if not only, cause of Sotos syndrome, a developmental abnormality marked by bone overgrowth, craniofacial defects, learning disabilities, and a spectrum of other disorders. Translocations at chromosome 4 can lead to defects in NSD2 and the developmental disorder known as Wolf Hirschhorn syndrome. Additional pathologies caused by perturbations in the NSD family have also been noted.
Although highly relevant to human health and disease, surprisingly only a few details have been published regarding the mechanism of NSD family action. NSD family members are large proteins that possess numerous domains, many of which have been implicated in chromatin biology. Notably, NSD family members possess a catalytic SET domain that has been shown to methylate histone side chains, particularly lysine 36 of histone H3 (H3K36). Methylation at H3K36 has been reported to influence several processes including transcription, splicing, and even the DNA damage response. Additional studies have revealed that in response to tumor necrosis factor α or interleukin-1, NSD1 is activated and methylates two lysine residues in the p65 subunit of NF-κB, a critical factor in numerous cell systems. Thus, NSD1, and by, extension additional family members, also target non-histone proteins. The nature of these substrates and the pathways that they lie upon promise to be important in any of the numerous pathologies linked to the NSD family.
Our lab has created various research tools to understand the role of the NSD family in development and disease. Using a recently described "FLAG knock-in" strategy, we determined the global targets of NSD1. We found that NSD1 dependent methylation of H3K36 recruits RNA Polymerase II to various promoter elements including that of bone morphogenic protein 4 (BMP4). We are currently examining the relationship between H3K36 methylation and RNA Pol II activity.
Wagner, E. J. and Carpenter, P.B. (2011) Understanding the Language of Lysine 36 Methylation at Histone H3. Nature Reviews Mol Cell Biol. In press.
Lucio-Eterovic, A.K. and Carpenter, P.B. (2011) An open and shut case for the role of NSD proteins as oncogenes. Transcription. 2:158-161.
Eterovic, A.K., Adams, M.M., Gardner, J., Rice. J.C., and Carpenter, P.B. (2010) Role for the NSD1 methyltransferase in coordinating H3-K36 methylation with RNA Polymerase II function. Proc. Natl Acad. Sci. USA 107:16952-16957.
Dou, H., Huang, C., Adams, M.M., Carpenter, P.B., and Yeh, E.T.H. (2010) Regulation of DNA replication and repair through SUMOylation and de-SUMOylation of replication protein A complex. Molecular Cell 39: 333-345.
Rai, R., Zheng, H., He, H., Luo, Y., Cosme-Blanco, W., Multani, A., Carpenter, P.B., and Chang, S. (2010) The role of classical and alternative non-homologous end joining pathways in the repair of dysfunctional telomeres. EMBO J. 29: 2598-2610.
Program in Biochemistry and Molecular Biology
Office: MSB 6.200
Title: Associate Professor
Ph.D. - University of Illinois-Urbana Champaign - 1994