Kishor K. Bhakat, Ph.D., Assistant Professor
The role of posttranslational modification of proteins involved in cell signaling and transcription has been extensively investigated. However, the physiological significance of posttranslational modification of DNA repair proteins is not well understood. We found that many DNA repair proteins such as human AP-endonuclease (APE1/Ref-1), 8-oxoguanine DNA glycosylase (OGG1) and recently identified Nei-like glycosylases (NEIL1 and NEIL2) are acetylated both in vivo and in vitro by p300.
AP-endonuclease (APE) plays a central role in repair of most genomic damage induced by endogenous and reactive oxygen species. The mammalian APE (APE1/Ref-1) has two functions in transcriptional regulation: indirectly as an activator of transcription factors, and directly as a transcription factor. Besides activating some transcription factors, APE1 is directly involved in Ca2+-dependent downregulation of parathyroid hormone (PTH) and renin expression by binding to negative calcium response elements (nCaREs) present their promoter. We have shown that acetylation of APE1 enhances its binding to nCaRE-B in PTH gene and acts as repressor in calcium-dependent downregulation of PTH gene. Thus acetylation APE1 acts as a novel molecular switch for this key repair protein action in transcriptional regulation. Chronic elevated blood pressure of APE1 heterozygous mice implicates APE1 in blood pressure homeostasis in which renin also plays a key role via its activity in processing angiotensinogen. Moreover we recently discovered that acetylation of APE1 is essential for cell survival. Currently the focus of our research is to identify the in vivo binding partner(s) of APE1 and to investigate how acetylation modulates nCaRE and SSRE (Shear Stress Response Element) dependent genes expression including human renin gene. Our long-term goal is to understand how the transcriptional regulatory function of APE1 helps control blood pressure, particularly by modulating renin gene expression.
