Ataxia-Telangiectasia (A-T) is caused by mutations in the ATM gene. The primary function of ATM is to coordinate cellular responses to DNA damage including cell cycle checkpoints, DNA repair, and apoptosis. The clinical phenotypes in A-T patients including cancer predisposition, immune deficiencies, and neurological degeneration are caused by defective DNA damage responses. ATM is activated by DNA damage induced by environmental and endogenous genotoxins or caused by aberrant DNA metabolism. The ATM response to genotoxic agents has been heavily studied and is important to maintain the genome and prevent cancer. However, the ATM response to DNA lesions caused by alterations in gene function that result in aberrant DNA metabolism is also critical. For example, decreased expression of BRCA1, Rb, DDB1, or DNMT1 or overexpression of cyclin E, Cdt1, or Myc all cause ATM activation. Many of these genes act as tumor suppressors or oncogenes in cancer, and ATM promotes apoptosis or senescence in response to the DNA damage created by their deregulation in precancerous lesions. Thus, defects in the DNA damage response (such as mutations in ATM) facilitate the maintenance and propagation of cells containing genetic alterations that perturb genome integrity. The objective of this research is to identify the biological processes and genes that are required to maintain genome integrity and whose deregulation promotes cancer initiation. Identifying these genes will improve our understanding of the cancer barrier function of ATM. To accomplish this goal, we will (1) identify genes whose deregulation activates ATM, and (2) validate and classify these genes into functional categories.This project will define cellular mechanisms that maintain genome integrity. These mechanisms are critical to prevent cancer. Thus, completion of the research will help explain the causes of cancer especially with regard to the disease Ataxia-Telangiectasia.
| Wiltshire, Timothy D; Lovejoy, Courtney A; Wang, Tong et al. (2010) Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol Chem 285:14565-71 |
| Lovejoy, Courtney A; Xu, Xin; Bansbach, Carol E et al. (2009) Functional genomic screens identify CINP as a genome maintenance protein. Proc Natl Acad Sci U S A 106:19304-9 |
| Bansbach, Carol E; Bétous, Rémy; Lovejoy, Courtney A et al. (2009) The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev 23:2405-14 |
| Bhaskara, Srividya; Chyla, Brenda J; Amann, Joseph M et al. (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell 30:61-72 |
| Cimprich, Karlene A; Cortez, David (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9:616-27 |
