Tale of a multifaceted co-activator, hADA3: from embryogenesis to cancer and beyond

Abstract

Human ADA3, the evolutionarily conserved transcriptional co-activator, remains the unified part of multiple cellular functions, including regulation of nuclear receptor functions, cell proliferation, apoptosis, senescence, chromatin remodelling, genomic stability and chromosomal maintenance. The past decade has witnessed exciting findings leading to considerable expansion in research related to the biology and regulation of hADA3. Embryonic lethality in homozygous knockout Ada3 mouse signifies the importance of this gene product during early embryonic development. Moreover, the fact that it is a novel target of Human Papillomavirus E6 oncoprotein, one of the most prevalent causal agents behind cervical cancer, helps highlight some of the crucial aspects of HPV-mediated oncogenesis. These findings imply the central involvement of hADA3 in regulation of various cellular functional losses accountable for the genesis of malignancy and viral infections. Recent reports also provide evidence for post-translational modifications of hADA3 leading to its instability and contributing to the malignant phenotype of cervical cancer cells. Furthermore, its association with poor prognosis of breast cancer suggests intimate association in the pathogenesis of the disease. Here, we present the first review on hADA3 with a comprehensive outlook on the molecular and functional roles of hADA3 to provoke further interest for more elegant and intensive studies exploring assorted aspects of this protein.

Keywords: ADA3; cancer; co-activator; development; genomic stability.

Figure 1.

Discovery of ADA3 and its consequential role in transcriptional activation. ADA3 was isolated as a transcriptional co-activator using a Gal4-VP16 system, where removal of ADA3 disrupted transcriptional activation by abrogating the ADA3-mediated bridging interaction between the general factors and the distal activators.

Figure 2.

Function of hADA3 as a co-activator. hADA3 is part of the BTM and acts as a transcriptional co-activator to conduit the UAS to the BTM for the transcriptional activation of p53, ER, RAR, RXR, etc., in order to regulate various cellular functions that are crucial for normal cellular growth.

Figure 3.

The role of hADA3 in DDR. As a consequence of DNA damage, hADA3 gets activated, followed by initiation of a downstream activation cascade of key mediators of DDR regulated via p300/CBP complex, PCAF and GCN5. The ultimate fate is either DNA repair, if possible, or cellular death.

Figure 4.

In silico prediction of potential sites of hADA3 PTM. Different PTM of hADA3 have been depicted with possible residues of modification for ubiquitination, acetylation, SUMOylation and phosphorylation.

Figure 5.

Putative hADA3 signalling pathways. hADA3 functions are regulated through a complex network of signalling pathways, some signals including hormones, genotoxic stress or several classes of proteins like oncoproteins and tumour suppressors, to facilitate an assortment of biological activities related to cell cycle arrest, apoptosis, senescence, cell proliferation and differentiation.

Figure 6.

Involvement of HPV16E6 oncoprotein in vitiation of hADA3 mediated functions. HPV16E6 oncoprotein, through its hijacking of hADA3, agitates the normal functions of several transcription modulators such as p300 and PCAF, causing deregulation of numerous TF, thus affecting a multitude of imperative physiological process culminating in tumorigenesis.