Cancer cells, unlike normal cells, over-express the genes that are involved in replication. The transcription factors of the E2F family (E2Fs) are centrally important in this regard because they regulate expression of several key genes that are essential for replication and cell cycle progression. Also, E2Fs are targets of oncogenes, tumor suppressor genes and cell cycle regulators. Cellular pathways that control E2Fs are frequently mutated in human cancers, suggesting that they play critical roles in preventing oncogenesis. The goal of this proposal is to elucidate the mechanisms by which E2Fs control expression of the replication genes, which will be extremely valuable in designing therapeutic interventions. The proposal is based on the observation that DDB (which was identified as an activity that binds UV-damaged DNA) functions as a transcription partner of the E2F-family factor E2F1. DDB binds to the activation domain of E2F1 and stimulates E2F1-activated transcription. Moreover, expression of DDB overcomes the transcriptional inhibitory function of the Rb tumor suppressor. We propose to investigate the hypothesis that DDB is important for the regulated expression of the replication genes t the G1/S-phase boundary. Furthermore, the mechanism by which DDB stimulates transcription and overcomes Rb-inhibition will be investigated.
The specific aims are: 1. Is DDB essential for the E2F1-activated expression of the replication genes? 2. Is DDB a target of the cell cycle regulators such as p16Ink4a, p27Kip1 and p21Cip1? Does DDB compete with the tumor suppressor Rb for E2F1? 3. What is the mechanism by which DDB cooperates with E2F1 to stimulate transcription? 4. Is E2F1-DDB interaction regulated by damaged-DNA?
| Fantini, Damiano; Huang, Shuo; Asara, John M et al. (2017) Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2. Mol Biol Cell 28:192-200 |
| Roy, Nilotpal; Bommi, Prashant V; Bhat, Uppoor G et al. (2013) DDB2 suppresses epithelial-to-mesenchymal transition in colon cancer. Cancer Res 73:3771-82 |
| Roy, Nilotpal; Elangovan, Indira; Kopanja, Dragana et al. (2013) Tumor regression by phenethyl isothiocyanate involves DDB2. Cancer Biol Ther 14:108-16 |
| Roy, Nilotpal; Bagchi, Srilata; Raychaudhuri, Pradip (2012) Damaged DNA binding protein 2 in reactive oxygen species (ROS) regulation and premature senescence. Int J Mol Sci 13:11012-26 |
| Stoyanova, Tanya; Roy, Nilotpal; Bhattacharjee, Shaumick et al. (2012) p21 cooperates with DDB2 protein in suppression of ultraviolet ray-induced skin malignancies. J Biol Chem 287:3019-28 |
| Raychaudhuri, Pradip; Park, Hyun Jung (2011) FoxM1: a master regulator of tumor metastasis. Cancer Res 71:4329-33 |
| Kopanja, Dragana; Roy, Nilotpal; Stoyanova, Tanya et al. (2011) Cul4A is essential for spermatogenesis and male fertility. Dev Biol 352:278-87 |
| Dominguez-Brauer, Carmen; Brauer, Patrick M; Chen, Yi-Ju et al. (2010) Tumor suppression by ARF: gatekeeper and caretaker. Cell Cycle 9:86-9 |
| Roy, Nilotpal; Stoyanova, Tanya; Dominguez-Brauer, Carmen et al. (2010) DDB2, an essential mediator of premature senescence. Mol Cell Biol 30:2681-92 |
| Dominguez-Brauer, Carmen; Chen, Yi-Ju; Brauer, Patrick M et al. (2009) ARF stimulates XPC to trigger nucleotide excision repair by regulating the repressor complex of E2F4. EMBO Rep 10:1036-42 |
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