PhD. Dissertation Defense: Nazlı Keskin | Mühendislik ve Doğa Bilimleri Fakültesi

IDENTIFICATION OF PATZ1 TRANSCRIPTION FACTOR AS A NOVEL INTERACTING PARTNER AND REGULATOR OF THE p53 TUMOR SUPPRESSOR PROTEIN

Nazlı KESKİN

Biological Sciences and Bioengineering, PhD Dissertation, 2014

Thesis Jury

Assoc.Prof.Dr Batu Erman (Thesis Advisor), Assoc.Prof.Dr. Devrim Gözüaçık, Assist. Prof.Dr. Özge Akbulut, Prof.Dr. Selim Çetiner, Assoc.Prof.Dr. Uygar Halis Tazebay

Date & Time: July 23rd, 2014 – 11:00 AM

Place: FENS L027

Keywords: cancer, p53, PATZ1, transcription factor, DNA damage

Abstract

The tumor suppressor p53 is a stres responsive, sequence specific transcription factor that regulates genes controlling the cell cycle, senescence and apoptosis. Mutation of p53 is the most common genetic event in human cancer. Moreover, p53 deficiency results in the accumulation of different tumor types such as testicular carcinoma, soft tissue sarcoma and lymphoma in mice. The focus of this study, PATZ1 transcription factor, has diverse roles in cancer, development and stem cell biology. Besides being a key transcription factor in lymphocyte development, PATZ1 expression is misregulated in different tumor types such as testicular, colorectal and breast cancers.

Because both proteins are significant modifiers of human cancer, we aimed to link the PATZ1 protein to p53 function using a biochemical approach. In this study, we discovered that both overexpressed and endogenous p53 and PATZ1 proteins interact. We identified a p53 binding region in the C-terminal domain of the PATZ1 protein. The interaction between PATZ1 and p53 is specific, as an alternative splice variant, PATZ1Alt, which lacks this region, did not bind p53. We further delineated the interaction region by generating site directed point mutant PATZ1 variants which do not bind p53. The p53 – PATZ1 interaction is functionally significant as neither p53 nor PATZ1 can bind DNA in the presence of the other factor. Therefore, p53 and PATZ1 form a complex that is incapable of DNA binding. We examined the cellular responses controlled by p53 in cells overexpressing PATZ1. Treatment with the DNA damage inducing cytotoxic drug doxorubicin activates p53 related pathways. Overexpression of PATZ1 made cells more resistant to death by doxorubicin treatment. This study documents a novel player in the p53 pathway, a suppressor transcription factor, PATZ1.