Abstract 2719: ADA3, a cell cycle regulator, regulates chromosome segregation

The RNA polymerase II mediated transcription requires the higher degree structure of chromatin to be relieved so that general transcription machinery can access the DNA. The acetylation of DNA bound histones at specific loci is the major epigenetic modification by which opening of chromatin is achieved. HATs (Histone Acetyl Transferase) are the enzymes that catalyze the acetylation of histones and require association with mediator proteins for their function. One such mediator protein is ADA3 (Alteration/Deficiency in Activation 3), which was initially discovered as a component of multi-protein complex that contains either GCN5 (General Control Non-repressed 5) or PCAF (p300/CBP Associated Factor) as HAT and subsequent studies showed that ADA3 associates with another HAT, p300. As a HAT interacting protein, ADA3 enhances the acetylation of histones as well as non-histone proteins, such as p53. We have recently shown that ADA3 is a cell cycle regulatory protein and is important for both G1 to S phase transition as well as mitosis. Conditional deletion of Ada3 from Ada3FL/FL MEFs (Mouse Embryonic Fibroblasts) causes cell cycle arrest and severe mitotic defects. To further explore the mechanism of ADA3 mediated mitosis, we performed ChIP-seq analyses and found that ADA3 bound to higher order repeat region of the centromere across most of the chromosomes. Further studies showed ADA3 interaction with centromere was mediated by a centromeric protein CENP-B. More importantly, siRNA mediated knockdown of ADA3 decreases the occupancy of CENP-B at centromere and causes chromosomal segregation defects during mitosis. These studies demonstrate a novel function of ADA3 in cell cycle regulation. Our current studies are focused on defining the exact mechanism of recruitment of ADA3 complex to CENP-B to regulate mitosis and its effect on genomic stability. Citation Format: Shashank Srivastava, Shakur Mohibi, June Wang-France, Sameer Mirza, Xiangshan Zhao, Hamid Band, Vimla Bnad. ADA3, a cell cycle regulator, regulates chromosome segregation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2719.