The primary objective of this project is to investigate the molecular link between the activation of DNA damage checkpoint in the nucleus and the initiation of apoptotic program resides in the cytoplasm. Cell-cycle checkpoints induce cell cycle arrest, DNA repair, and apoptotic responses in cells exposed to genotoxic stress. The tumor suppressor p53 has been established to play a central role in mediating these specific cellular responses. However, it remains to be determined whether other molecular events coordinated with p53 to couple the initial checkpoint activation in response to extensive DNA damage to the initiation of the apoptotic cascade. Recently, we discovered that Rad17, a component of the DNA damage/replication stress checkpoint pathway, directly relays a signal initiated by irreparable levels of DNA damage in the nucleus to the apoptotic machinery in the cytoplasm. Built on this discovery, we will focus our study on the following two aims:
Aim 1 will fully characterize the molecular nature of this novel apoptotic signaling pathway in response to DNA damage.
Aim 2 will determine the functional relationship between the Rad17- and p53-mediated apoptotic pathways in response to different degrees of DNA damage. Recent evidence indicates that activation of the checkpoints is associated with cells within the pre-cancerous lesions adjacent of areas containing fully transformed tumor cells, suggesting that disruption of checkpoint control is linked directly to carcinogenesis. Accomplishment of these goals will significantly advance our understanding of the mechanisms of checkpoint signaling and provide the molecular basis for the rational design of novel therapeutics to target checkpoint function for the treatment of cancers. ? ? ?
| Wakeman, Timothy P; Wang, Qinhong; Feng, Junjie et al. (2012) Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases. EMBO J 31:2169-81 |
| Yong, Sheila T; Wang, Xiao-Fan (2012) A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle. PLoS One 7:e38085 |
| Feng, Junjie; Wakeman, Timothy; Yong, Sheila et al. (2009) Protein phosphatase 2A-dependent dephosphorylation of replication protein A is required for the repair of DNA breaks induced by replication stress. Mol Cell Biol 29:5696-709 |
| Jardim, Melanie J; Wang, Qinhong; Furumai, Ryohei et al. (2009) Reduced ATR or Chk1 expression leads to chromosome instability and chemosensitization of mismatch repair-deficient colorectal cancer cells. Mol Biol Cell 20:3801-9 |
| Guo, Jessie Yanxiang; Yamada, Ayumi; Kajino, Taisuke et al. (2008) Aven-dependent activation of ATM following DNA damage. Curr Biol 18:933-42 |
