The overall goal of the research of the group is to provide a better understanding of the regulatory networks that control critical cellular responses to environmental stresses. We are currently investigating cell cycle checkpoint responses to cellular damage from various environmental stresses and how defects in these responses can contribute to cancer. Intricate regulatory networks control stress-induced cell cycle checkpoints and these networks respond in a damage- and cell type-specific manner. Group members are presently studying the critical molecular events that regulate cell cycle checkpoint signaling following exposures to ionizing radiation (IR), ultraviolet (UV) radiation, oxidative stress and other environmental stresses. In addition, we are investigating the cellular specificity of these processes in normal human cells (e.g. normal breast epithelial cells) and cells with genetic alterations in cancer susceptibility genes, such as the gene mutated in ataxia telangiectasia (ATM). Three independent isogenic lines of normal and ATM-deficient breast epithelial cells have been established through stable shRNA knock-down techniques in order to obtain populations of mammary epithelial cells that differ only in their levels of ATM. In addition, isogenic normal and ATM-deficient mammary epithelial lines have been established that are deficient in the checkpoint kinase 1 (CHK1), as well as lines with a conditional depletion of the kinase function of the ATM and Rad3-related kinase (ATR). Studies of DNA damage signaling in these cells has provided novel mechanistic insight into the function of ATM, ATR, and CHK1 protein kinases and the DNA-dependent protein kinase (DNA-PK) in the G2 checkpoint response to ionizing radiation induced cellular damage. In studies performed in collaboration with Barry Sleckman and colleagues, we have investigated the gene expression responses and signaling pathways activated by genotoxic radiation-induced DNA damage in mouse pre-B cells that are from mouse strains that are deficient in various DNA damage response and repair genes. We have been able to show that in addition to the expected cell cycle checkpoint and DNA damage and repair responses, these double strand breaks also initiate, in part, an overlapping lymphocyte-specific genetic program that contributes to B-cell development and differentiation, as we had previously found following physiological Rag-mediated double strand breaks. We have also found that there is a cell-cycle dependent immune activation response following radiation induced DNA damage.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2012
Total Cost
$1,095,860
Indirect Cost
City
State
Country
Zip Code
Omolo, Bernard; Carson, Craig; Chu, Haitao et al. (2013) A prognostic signature of G(2) checkpoint function in melanoma cell lines. Cell Cycle 12:1071-82
Palii, Stela S; Cui, Yuxia; Innes, Cynthia L et al. (2013) Dissecting cellular responses to irradiation via targeted disruptions of the ATM-CHK1-PP2A circuit. Cell Cycle 12:1105-18
Zhang, Liwen; Simpson, Dennis A; Innes, Cynthia L et al. (2013) Gene expression signatures but not cell cycle checkpoint functions distinguish AT carriers from normal individuals. Physiol Genomics 45:907-16
Hesse, Jill E; Liu, Liwen; Innes, Cynthia L et al. (2013) Genome-wide small RNA sequencing and gene expression analysis reveals a microRNA profile of cancer susceptibility in ATM-deficient human mammary epithelial cells. PLoS One 8:e64779
Innes, Cynthia L; Hesse, Jill E; Palii, Stela S et al. (2013) DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs. BMC Genomics 14:163
Fu, Dragony; Brophy, Jennifer A N; Chan, Clement T Y et al. (2010) Human AlkB homolog ABH8 Is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival. Mol Cell Biol 30:2449-59
Bower, Jacquelyn J; Zhou, Yingchun; Zhou, Tong et al. (2010) Revised genetic requirements for the decatenation G2 checkpoint: the role of ATM. Cell Cycle 9:1617-28
Arlander, Sonnet J H; Greene, Bryan T; Innes, Cynthia L et al. (2008) DNA protein kinase-dependent G2 checkpoint revealed following knockdown of ataxia-telangiectasia mutated in human mammary epithelial cells. Cancer Res 68:89-97