The major objectives of this application are to: (i) functionally characterize a signal transduction pathway linking ATM (ataxia-telangiectasia-mutated) to the cyclic AMP response element-binding protein (CREB) transcription factor;and (ii) identify and functionally characterize novel ATM substrates. ATM is a DNA damage-activated protein kinase that is mutated in the genetic instability and neurodegeneration syndrome, ataxia-telangiectasia, whereas CREB is a neuroprotective transcription factor that regulates cell growth, metabolism, and survival. We have defined a new mode of CREB regulation whereby ATM and casein kinases 1 and 2 (CK1/CK2) collaboratively phosphorylate CREB on five clustered sites termed the RAX domain (co-Regulated ATM and Casein Kinase Sites) in response to genotoxic stress. Phosphorylation of CREB by ATM and CK1/CK2 inhibits the interaction between CREB and its coactivator, CREB-binding protein (CBP) suggesting that the ATM pathway may repress CREB transcriptional functions in response to DNA damage. The linkage between ATM and CREB is intriguing given the neuroprotective functions of both factors. In this proposal we will test the hypothesis that ATM plays a dual role in CREB regulation through suppression and stimulation of RAX domain phosphorylation in unperturbed and DNA-damaged cells, respectively. An important goal of the work is to define the upstream signals controlling CREB RAX domain phosphorylation in the absence of DNA damage and to elucidate the biochemical outcomes of its modification in intact cells. In addition, we will use information gleaned from the CREB phosphorylation paradigm to discover and functionally characterize protein substrates that are coordinately regulated by ATM and CK1/CK2 in response to DNA damage. These studies should yield fundamental insights into the mechanisms of ATM function and CREB regulation, and may alter current views of ATM signaling in response to DNA damage. The goal of this project is to understand the molecular basis for the neurodegeneration/cancer susceptibility syndrome, ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene. ATM is a critical regulator of cellular responses to DNA damage and the work proposed in this application will characterize a particularly important downstream target of ATM, termed CREB (cyclic AMP response element-binding protein), which is an important regulator of gene expression. We are specifically interested in examining whether deregulation of CREB contributes to the manifestation of A-T-related phenotypes, including cancer, and neuron demise.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Medicine
United States
Zip Code
Trinh, Anthony T; Kim, Sang Hwa; Chang, Hae-yoon et al. (2013) Cyclin-dependent kinase 1-dependent phosphorylation of cAMP response element-binding protein decreases chromatin occupancy. J Biol Chem 288:23765-75
Shanware, Naval P; Hutchinson, John A; Kim, Sang Hwa et al. (2011) Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem 286:12766-74
Hutchinson, John A; Shanware, Naval P; Chang, Haeyoon et al. (2011) Regulation of ribosomal protein S6 phosphorylation by casein kinase 1 and protein phosphatase 1. J Biol Chem 286:8688-96
Shanware, Naval P; Zhan, Lihong; Hutchinson, John A et al. (2010) Conserved and distinct modes of CREB/ATF transcription factor regulation by PP2A/B56gamma and genotoxic stress. PLoS One 5:e12173
Sakasai, Ryo; Teraoka, Hirobumi; Takagi, Masatoshi et al. (2010) Transcription-dependent activation of ataxia telangiectasia mutated prevents DNA-dependent protein kinase-mediated cell death in response to topoisomerase I poison. J Biol Chem 285:15201-8
Sakasai, Ryo; Teraoka, Hirobumi; Tibbetts, Randal S (2010) Proteasome inhibition suppresses DNA-dependent protein kinase activation caused by camptothecin. DNA Repair (Amst) 9:76-82
Kim, Sang Hwa; Shanware, Naval P; Bowler, Michael J et al. (2010) Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285:34097-105
Hanson, Keith A; Kim, Sang Hwa; Wassarman, David A et al. (2010) Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J Biol Chem 285:11068-72
Kim, Sang Hwa; Shi, Yuling; Hanson, Keith A et al. (2009) Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. J Biol Chem 284:8083-92