Lab overview:

My lab studies molecular mechanisms of genome surveillance and neurodegeneration.  Much of the work in our group centers around a protein kinase termed ATM (ataxia-telangiectasia-mutated) that is mutated in the genetic instability/neurodegeneration syndrome, ataxia-telangiectasia (A-T).  ATM is a DNA damage-activated kinase that regulates a vast network of proteins, including the p53, CHEK2, and BRCA1 tumor suppressors, which promote the activation of cell cycle checkpoints and initiation of DNA repair.  Mutations in ATM lead to global defects in the cellular response to DNA damage and, as a consequence of these abnormalities, A-T patients are hypersensitive to ionizing radiation (IR) and highly susceptible to cancer development.    A-T patients also exhibit progressive loss of Purkinje cells in the cerebellum, which leads to severe physical disability.

The identification of novel ATM-regulated represents one major focus area of our group.  We have discovered that two members of the cyclic AMP response binding protein (CREB) family of transcription factors, CREB1 and ATF1, are phosphorylated by ATM on a stress-inducible (S-I) domain and, because CREB proteins are required for neuron survival, we are interested in the possibility that deregulation of these factors contributes to neurodegeneration in A-T.  This is being tested using cell based approaches and in vivo using a CREB gene knock-in model constructed in our lab.  In a related project, we are exploring pathways that control S-I domain phosphorylation in the absence of DNA damage.  We think that this pathway may control CREB activity in response to metabolic cues. 

We are also interrogating the mechanisms of neurodegeneration in A-T collaboratively with Dr. David Wassarman in The Department of Pharmacology.  The Wassarman laboratory has established a fruit fly (Drosophila melanogaster) model for A-T and, through a series of genetic screens, identified several genes that modify the severity of neurodegeneration.  Interestingly, inactivating mutations in genes that promote cell cycle progression rescued neurodegeneration in ATM-deficient flies, suggesting that aberrant cell cycle entry in the absence of ATM causes neuron death.  We are now testing this hypothesis in mouse models with the hope of developing a better mouse model for A-T.  Finally, more recent work in the lab has expanded into another neurodegenerative condition, amyotrophic lateral sclerosis (ALS), which is characterized by paralysis consequent to the death of motor neurons.  Aggregation promoting mutations in an RNA-binding protein named TDP-43 have recently been linked to ALS, and we are interested in the biochemical basis for TDP-43 aggregation.

• Sakasai R and Tibbetts RS. (2008). RNF8-dependent and independent regulation of 53BP1 in response to DNA damage. J Biol Chem. 83:3549-55.

• Rimkus SA, Katzenberger RJ, Trinh AT, Dodson GE, Tibbetts RS, and Wassarman DA. (2008). Mutations in string/CDC25 inhibit cell cycle reentry and neurodegeneration in a Drosophila model of ataxia-telangiectasia Genes Dev. 22:1205-20.

• Shanware NP, Trinh AT, Williams LM, and Tibbetts RS.  (2007). Coregulated ATM and casein kinase sites modulate CREB-coactivator interactions in response to DNA damage. J Biol Chem. 282:6283-6291. PDF PMID 17209043
  
  
• Shi Y, Dodson GE, Mukhopadhyay P, Shanware NP, Trinh AT, and Tibbetts RS. (2007). Identification of carboxyl-terminal MCM3 phosphorylation sites using polyreactive phospho-specific antibodies. J Biol Chem. 282:9236-9243. PDF PMID 17244605
  
  
• Wu ZH, Shi Y, Tibbetts RS, Miyamoto S. (2006). Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science. 311:1141-1416. PDF PMID 16497931
  
  
• Dodson GE and Tibbetts RS. (2006). DNA replication stress-induced phosphorylation of cyclic AMP response element-binding protein mediated by ATM. J Biol Chem. 281:1692-1697. PDF PMID 16293623
  
  
• Shi Y, Dodson GE, Shaikh S, Rundell K, and Tibbetts RS. (2005). Ataxia-telangiectasia-mutated (ATM) is a T-antigen kinase that controls SV40 viral replication in vivo. J Biol Chem. 280:40195-200. PDF PMID 16221684
   
  
• Kumar S, Dodson GE, Trinh A, Puchalski JR, and Tibbetts RS. (2005). ATR activation necessary but not sufficient for p53 induction and apoptosis in hydroxyurea-hypersensitive myeloid leukemia cells. Cell Cycle. 4:1667-74. PMID 16258278
   
• Abraham RT and Tibbetts RS. (2005) Guiding ATM to broken DNA. Science. 308:510-511 (perspective). PMID 15845843
   
• Dodson GE, Shi E, and Tibbetts RS. (2004). DNA replication defects, spontaneous DNA damage, and ATM-dependent checkpoint activation in replication protein A-deficient cells. J Biol Chem. 279:34010-34014. PDF PMID 15197179
   
• Brumbaugh KM, Otterness DM, Geisen G, Oliveira V, Brognard J, Li X, LeJeune F, Tibbetts RS, Maquat L, and Abraham RT. (2004). The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. Mol Cell. 14:585-98. PDF PMID 15175154
   
• Shi Y, Venkataraman S, Dodson GE, Mabb AM, LeBlanc S, and Tibbetts RS. (2004). Direct regulation of CREB transcriptional activity by ATM in response to DNA damage. PNAS 101:5898-5903. PDF PMID 15073328

Lab Members:

• Elli Shi, Ph.D. (postdoc)
• Ryo Sckasai, Ph.D. (post doc)
• Tony Trinh (graduate student)
• Naval Shanware (graduate student)
• Leah Williams (technician)
• Sang Hwa Kim, Ph.D. (postdoc)
• John Hutchinson (graduate student)
• Keith Hanson (MSTP student)
• Lihong Zhan (graduate student)
• Mike Bowler (undergraduate)

• Sujatha Kumar, Ph.D. (graduated 2006)
• Gerald Dodson, Ph.D. (graduated 2006)
• Peter Seebart (undergraduate, 2003-2005)

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