Eukaryotic cells respond to DNA damaging events, such as gamma-irradiation exposure, by halting cell cycle progression, and activating DNA repair mechanisms. In the case of irreparable DNA damage, cells also respond by initiating programmed cell death or apoptosis. Not surprisingly, defects in these responses often result in gene mutation, chromosomal aberrations, which in turn can lead to malignancy. Sitting at the top of the signaling networks induced by IR, and orchestrating these responses is the product of the gene that is mutated in Ataxia Telangiectasia (ATM). Studies from the principal investigator's laboratory determined that, despite its structural similarity to lipid kinases, ATM displays protein kinase activity. Further, when activated by ionizing radiation (IR), ATM activates the c-Abl tyrosine kinase via direct phosphorylation. ATM-activated Abl subsequently phosphorylates RNA polymerase II (RNAP II) on its C-terminal repeated domain to modulate transcription of genes required for DNA damage responses. The major objective of this study is to extend our ongoing research focused on elucidating the functional significance of ATM to Abl to RNAP II signaling in genome damage response. To accomplish the objective, the proposed specific aims are: a) determine the role of ATM-activated Abl in cell cycle checkpoint activation, b) determine the role of ATM-activated Abl in JR-induced apoptosis and DNA repair responses, and c) decipher the functional significance of RNAP II tyrosine phosphorylation in genome damage responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060945-05
Application #
6943008
Study Section
Biochemistry Study Section (BIO)
Program Officer
Zatz, Marion M
Project Start
2001-09-10
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2005
Total Cost
$222,750
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Jiang, Zhihua; Kamath, Ravindra; Jin, Shunquian et al. (2011) Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. Mol Cancer 10:88
Jiang, Zhihua; Jin, ShunQian; Yalowich, Jack C et al. (2010) The mismatch repair system modulates curcumin sensitivity through induction of DNA strand breaks and activation of G2-M checkpoint. Mol Cancer Ther 9:558-68
Sun, Guoming; Jin, Shunqian; Baskaran, R (2009) MMR/c-Abl-dependent activation of ING2/p73alpha signaling regulates the cell death response to N-methyl-N'-nitro-N-nitrosoguanidine. Exp Cell Res 315:3163-75
Kamath, Ravindra; Jiang, Zhihua; Sun, Guoming et al. (2007) c-Abl kinase regulates curcumin-induced cell death through activation of c-Jun N-terminal kinase. Mol Pharmacol 71:61-72
Shangary, Sanjeev; Lerner, Edwina C; Zhan, Qimin et al. (2003) Lyn regulates the cell death response to ultraviolet radiation through c-Jun N terminal kinase-dependent Fas ligand activation. Exp Cell Res 289:67-76
Zhan, Qimin; Jin, Shunqian; Ng, Bobby et al. (2002) Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis. Oncogene 21:5335-45