The role of BTB/zinc finger transcription factor Patz1/MAZR in the regulation of p53-mediated DNA damage response during T cell development
Ün, Manolya (2011) The role of BTB/zinc finger transcription factor Patz1/MAZR in the regulation of p53-mediated DNA damage response during T cell development. [Thesis]
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T lymphocytes make up an important line of defense against invading pathogens and tumors, where the success of the immune response depends on the range of threats that can be identified properly. The diversity required for the antigen-specific T cell receptors (TCRs) is achieved through a biological mechanism called somatic V(D)J recombination, where double-stranded DNA breaks naturally occur as a result of gene rearrangements in the TCR gene loci during T cell development. The process is tightly regulated by the tumour suppressor p53 through the activation of several DNA damage checkpoints. To investigate how p53 controls T lymphocyte developmental checkpoints we studied its interaction with transcription factors known to be expressed in developing T cells. Using computer-stimulated computer modeling backed up by coimmunoprecipitation studies, we showed that Patz1/MAZR interacts with the basic Cterminal domain of p53 through an isoform 001-specific binding pocket generated by the 6th and the 7th C2H2-type zinc finger motifs that is not present in other alternatively spliced Patz1/MAZR isoforms. Furthermore, we demonstrated that residues Asp521 and Asp527 located in the binding pocket play a critical role for the interaction of p53 by site-directed mutagenesis. Cell survival assays performed in the immortalized human cell line HEK293T and DP mouse lymphoma cell lines AKR1 and VL3 showed that the Patz1/p53 interaction confers protection against cell death and inhibits p53-induced apoptosis.
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