Faculty: Randal S. Tibbetts
|Dept:||Associate Professor, Human Oncology|
|Contact:|| 3059 WIMR
1111 Highland Ave
|Lab Website:||Click Here|
Research projects in our lab broadly pertain to genomic surveillance, metabolic regulation, and molecular mechanisms of neurodegeneration in ALS. Current areas of focus include:
(i) Non-canonical regulation of CREB/ATF transcription factors: relevance to tumor suppression and metabolic homeostasis. Mutations in the ATM protein kinase cause ataxia-telangiectasia (A-T), a syndrome of cancer susceptibility and neurodegeneration that is characterized at the cellular level by profound radiation sensitivity and dramatically impaired ability to signal and repair DNA double-strand breaks. A-T patients and ATM-deficient mice also manifest metabolic abnormalities suggesting that ATM senses and responds to metabolic cues. We previously showed that ATM phosphorylates and inhibits the cAMP-regulated transcription factors CREB and ATF1 in response to DNA damage and other forms of cell stress. CREB and ATF1 have been intensively studied for their roles in glucose homeostasis/obesity and long-term potentiation of neuronal synaptic transmission in vivo. Interestingly, CREB gene-targeted mice in which CREB phosphorylation by ATM is abolished exhibit metabolic abnormalities similar to those seen in A-T. Ongoing studies are exploring mechanisms of CREB phosphorylation in the context of metabolic stress and how ATM signaling through CREB contributes to metabolic homeostasis. The CREB S111A model is also being used to investigate an emergent link between ATM, CREB, and the p53 tumor suppressor pathway.
(ii) Novel roles of roles of RNA-binding proteins in DNA repair. Also under the umbrella of genome protection, we are investigating how a family of multifunctional RNA-binding proteins, typified by the fused in sarcoma (FUS) protein participate in DNA double-strand break (DSB) repair. FUS is amongst the first proteins recruited to DSBs, is phosphorylated by ATM, and is required for the two major forms of DSB repair: non-homologous end joining (NHEJ) and homologous recombination (HR). We are currently investigating the molecular details of FUS-dependent DSB repair, which may have implications for human cancers harboring chromosomal translocations at the FUS gene locus and (see below), ALS.
(iii) Molecular cell biology of ALS-associated proteins. The third focus group in our lab studies molecular mechanisms of neurodegeneration in the motor neuron disease ALS. Recent genetic advances have identified a handful of genes whose mutation is sufficient to cause ALS, including the RNA-binding protein TDP-43, the uncharacterized open reading frame C9ORF72, the ubiquitin chaperone UBQLN2, and remarkably, FUS (though it is unclear whether DNA repair defects contribute to the development of ALS in FUS mutant patients.) We are using cell-based and in vitro approaches to understand how mutations in FUS, and UBQLN2 alter their normal cellular function and using a Drosophila model to understand how TDP-43 misexpression promotes neurodegeneration. The long-term goals of these studies are to define pathways that can be therapeutically targeted in ALS.
Our group pursues several areas of investigation broadly pertaining to signal transduction in cancer and neurodegenerative disease. One project involves understanding cellular responses to DNA damage in the context of ataxia-telangiectasia, a syndrome of cancer susceptibility and cerebellar neurodegeneration caused by mutations in the ATM gene. ATM is a tumor suppressor that fulfills a pervasive regulatory role in the DNA damage response through phosphorylation of DNA repair-, cell cycle-, and apoptosis-associated protein; however, ATM is also involved in many other aspects of cellular regulation.
Current lab members:
Sang Hwa Kim, Ph.D.
Adam Mastrocola, Ph.D.
Bennet Fox (graduate student)
Lihong Zhan (graduate student)
Mary Durston (graduate student)
Past lab members:
Sujatha Kumar, Ph.D. (MCP graduate student; 2001-2006)
Gerald Dodson, Ph.D. (graduate student; 2001-2006)
Naval Shanware, Ph.D. (MCP graduate student; 2004-2009)
Yuling Shi, Ph.D. (postdoctoral fellow; 2002-2007)
Ryo Sakasai, Ph.D. (postdoctoral fellow; 2006-2009)
Tony Trinh (MCP graduate student; 2006-2013)
Leah Williams (technician)
Keith Hanson (MSTP/MCP student; 2008-2011)
John Hutchinson (graduate student)
- Mastrocola AS, Kim SH, Trinh AT, Rodenkirch LA, and Tibbetts RS (2013). The RNA Binding Protein Fused In Sarcoma (FUS) Functions Downstream of PARP in Response to DNA Damage. J Biol Chem. 2013 Jul 5. [Epub ahead of print]
- Trinh AT, Kim SH, Chang H, Mastrocola AM, and Tibbetts RS (2013). Cyclin-dependent Kinase 1 Dependent Phosphorylation of cAMP Response Element Binding Protein Decreases Chromatin Occupancy. J. Biol. Chem. 288:23765-75. Epub 2013 Jun 27.
- Zhan L, Hanson KA, Kim SH, Tare A, and Tibbetts RS (2013). Identification of genetic modifiers of TDP-43 neurotoxicity in Drosophila. PLoS One. 8:e57214. Epub 2013 Feb 27. PMID: 23468938
- Kim SH, Zhan L, Hanson KA, and Tibbetts RS (2012). High-content RNAi screening identifies the Type1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity. Hum Mol Genet. 21:4845-56. Epub 2012 Aug 7. PMID: 22872699
- Hanson KA, Kim SH, and Tibbetts RS (2011). RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond.Wiley Interdiscip Rev RNA. 3:265-85. Epub 2011 Oct 25. Review. PMID: 22028183
- Shanware NP, Hutchinson JA, Kim SH, Zhan L, Bowler MJ, and Tibbetts RS (2011). Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem. 2286:12766-74. PMID: 21324900
- Hanson KA, Kim SH, and Tibbetts RS (2011). RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond. Wiley Interdiscip Rev RNA. PMID: 22028183
- Sakasai, R., Teraoka, H., Takagi, M., and Tibbetts RS (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 [PMID: 20304914]
- Hanson, K.A., Kim, S.H., Wassarman, D.A. and Tibbetts RS (2010). Ubiquilin modifies toxicity of the 43 kilodalton TAR-DNA binding protein (TDP-43) in a Drosophila model of amyotrophic lateral sclerosis (ALS). J. Biol. Chem. 285:11068-72 [PMID: 20154090]
- Sakasai, R. and Teraoka, H., and Tibbetts RS (2009). Proteasome inhibition suppresses DNA-dependent protein kinase activation caused by camptothecin. DNA Repair. 9:76-82 [PMCID: PMC2818427]
- Shanware, N.P., Williams, L.M., Bowler, M.B. and Tibbetts RS (2009). Non-specific in vivo inhibition of CK1 by the pyridinyl imidazole p38 inhibitors SB203580 and SB202190. BMB Reports. 42:142-147. [PMID: 19336000]