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Sun, Guoming (2009) ROLE OF ING2 (INHIBITOR OF GROWTH FAMILY MEMBER 2) IN CELLUAR RESPONSES TO DNA DAMAGE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Genome stability is essential for cells to survive. Consequently, cells have evolved intricate responses that include transcriptional changes, cell-cycle arrest, activation of DNA repair, and apoptosis. Such responses prevent permanent fixation of DNA damage induced by genotoxic agents into the genome, thus contributing to genome stability. A collection of proteins implicated in DNA damage responses are called Inhibition of Growth (ING) family, which are a group of small molecular weight proteins that regulate a variety of biological functions ranging from senescence, cell cycle arrest, apoptosis and DNA repair. ING proteins interact with Histone Acetyl-transferases (HAT) and Histone Deacetylases (HDAC) to alter the state of chromatin compaction and acetylation status of many proteins during DNA damage. A specific member of the ING family, ING2 has been implicated in modulating the tumor suppressor, p53 function through p300 HAT-mediated acetylation. Irradiation fails to upregulate ING2, but increases its association with transcription co-activator p300. That p300 HAT activation in the cells with ING2 knock down is hampered post-irradiation suggests that the interaction between ING2 and p300 is indispensable for the upregulation of the p300 HAT activity. Cells deficient in protein kinase Ataxia Telangiectasia Mutated (ATM) displays impaired p300 HAT activation and less association between p300 and ING2 following ionizing radiation, indicating that ATM function is also required. Alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) upregulates ING2 level in both time- and dose-dependent manner. We further observed that ING2 regulates the cell death response induced by this alkylator through a mechanism involving acetylation and stabilization of p73. Induction/acetylation of p53, in response to MNNG, however, proceeds in an ING2-independent manner. Inhibition of c-Abl by STI571 treatment blocked ING2 upregulation and p73 acetylation induced by MNNG. Similarly, MLH1- suppressed or mutated cells displayed defective ING2 upregulation and p73 acetylation in response to MNNG, which suggests that Mlh1- and c-Abl-dependent upregulation of ING2 activates the cell death response to MNNG through p73 acetylation.Taken together, these findings demonstrate that ING2 plays an important role in the cellular responses to different DNA damage by regulating the acetylation of tumor suppressors.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRajasekaran, Baskaranbask@pitt.eduBASK
Committee MemberZhang, LinZhangLx@upmc.eduLIZ22
Committee MemberSchmidt, Martinmcs2@pitt.eduMCS2
Committee MemberKhan, Saleemkhan@mgb.pitt.eduKHAN
Committee MemberCheng,
Date: 19 February 2009
Date Type: Completion
Defense Date: 16 January 2009
Approval Date: 19 February 2009
Submission Date: 18 February 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: acetylation; DNA damage; ING2; ionizing radiation; mismatch repair; MNNG
Other ID:, etd-02182009-224915
Date Deposited: 10 Nov 2011 19:31
Last Modified: 19 Dec 2016 14:34


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