The role of PATZ1 transcription factor in the DNA damage response
Deniz, Emre (2014) The role of PATZ1 transcription factor in the DNA damage response. [Thesis]
PATZ1 (MAZR) is a transcription factor composed of an N-terminal BTB protein-protein interaction domain and a C-terminal zinc finger and AT-hook DNA binding domain. Recent findings indicate that PATZ1 has a crucial role in the p53 pathway and during tumorigenesis. PATZ1 interacts with p53, is upregulated in various cancers and its absence favors lymphomagenesis. We identified a role for PATZ1 as a regulator of the p53 tumor suppressor protein. We found that upon doxorubicin induced DNA damage, the protein level of PATZ1 decreases, as the p53 protein accumulates. This inverse correlation between PATZ1 and p53 protein levels led us to investigate the biological relevance of these two proteins. We found that PATZ1 loss resulted in decreased proliferation rates in various cell types; while its overexpression accelerated proliferation. We demonstrate that PATZ1 inhibits the transcription activation function of p53 by luciferase reporter assays. While p53 is responsible for inducing the expression of the target genes p21 and Puma, we show that PATZ1 overexpressing cells cannot induce the expression of these genes as effectively as wild type cells. Finally, we performed genome scale RNA-Seq and microarray analysis on doxorubicin treated mouse embryo fibroblasts sufficient or deficient for PATZ1 and found that the absence of PATZ1 results in an alteration of the expression of p53 target genes. These results demonstrate that PATZ1 modulates p53-dependent cellular stress and DNA damage pathways.
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