| Post-DNA damage survival is regulated by ataxia-telengiectaia mutated (ATM) in the germinal center (GC) B-cell and is necessary for continued plasma cell development. Cell survival regulation is critical for the prevention of oncogenic transformation, as the gain of this trait is seen in many cancers. 90% of follicular lymphomas acquire resistance to apoptosis by a chromosomal translocation of the anti-apoptosis Bcl-2 gene onto the active IGH enhancer element. Bcl-2 is among a set of pro-survival genes that increase in expression at the end of a GC B-cell ATM initiated DNA damage response pathway; these genes will be referred to as DNA damage response (DDR) genes throughout this proposal. Gene ontology (GO) analysis of these genes indicates that they are involved in cellular proliferation, cellular physiological processes, cell cycle, and apoptosis. ChIP-chip data reveal CREB regulated transcription coactivator 2 (CRTC2) binding to these genes prior to DNA damage, suggesting that CRTC2 has a role to repress gene expression in the absence of damage stimulus. I hypothesize that CRTC2 has a novel role to repress pro-survival genes before DNA damage in GC B-cells, and that CRTC2 repressor function on Bcl-2 can reverse the transformed state of t(14;18)-positive lymphoma cells. These studies may point to CRTC2 as a novel tumor suppressor, and provide a new target for lymphoma therapy. |
