Functional Role of ATM-Ab1-RNAP II Signaling Pathway

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Cellular responses to DNA damage require a high degree of coordination between the DNA-damage sensing machinery and chromatin modification/ remodeling, which regulates the accessibility of DNA in chromatin. Recent studies have implicated a key role for acetyl transferases (HAT) and deacetylases (HDAC) in activation of DNA Damage signaling, repair and apoptotic responses, although the precise underlying mechanisms remain poorly understood. The proto-oncogene product, c-Abl tyrosine kinase, a downstream target of ATM (Ataxia Telangiectasia Mutated) exhibits pro-apoptotic activity, and in addition participates in DNA repair and transcription through RNAP II phosphorylation. Studies from our lab showed that ATMactivated Abl regulates cell death, DNA repair and transcriptional responses to genotoxic stress through modulation of p53, JNK, RNAP II and DNA-PK activity. We have recently found that c-Abl kinase is modified during DNA damage by acetylation mediated by TRRAP (transformation/transcription domain-associated protein)-binding partner, Tip60 acetyl-transferase. The identification of an LXXLL motif, found in many coactivators, HAT and p53, that interact with Tip60 as well as consensus acetylation sites (- K R K-X3-5- S G SK1- 3-E/G) in the C-terminus of c-Abl, support the view that c-Abl is a potential acetylation target. Moreover, we found that histone deacetylase (HDAC1) inhibitors (HDIs), Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) induced cell death in an Abl-dependent manner. This renewal application, an extension of our ongoing work on ATM and Abl, will test the hypothesis that TRRAP-associated Tip60 acetylates c-Abl in an ATM-dependent manner, consequently stimulating its kinase, apoptotic and/or DNA repair function. Specific aims are to: Aim I. Determine the functional consequence of Abl acetylation by Tip60 HAT. Aim II. Determine the DNA damage and ATM dependency of TRRAP/Tip60-induced Abl acetylation. Aim III. Elucidate the role of c-Abl in histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA)-induced apoptosis. Relevance: Greater insight into the cellular responses to stress is important for increased understanding of cancer in general, and for the development of new therapeutic treatments for individuals with dysfunctional DNA repair pathways.