Alteration/deficiency in activation-3 (Ada3) plays a critical role in maintaining genomic stability

作者：Mirza Sameer; Katafiasz Bryan J; Kumar Rakesh; Wang Jun; Mohibi Shakur; Jain Smrati; Gurumurthy Channabasavaiah Basavaraju; Pandita Tej K; Dave Bhavana J; Band Hamid; Band Vimla^*

来源：Cell Cycle, 2012, 11(22): 4266-4274.

DOI：10.4161/cc.22613

• Ada3
• ATAC
• SAGA
• nuclear foci
• DNA repair

Cell cycle regulation and DNA repair following damage are essential for maintaining genome integrity. DNA damage activates checkpoints in order to repair damaged DNA prior to exit to the next phase of cell cycle. Recently, we have shown the role of Ada3, a component of various histone acetyltransferase complexes, in cell cycle regulation, and loss of Ada3 results in mouse embryonic lethality. Here, we used adenovirus-Cre-mediated Ada3 deletion in Ada3(fl/fl) mouse embryonic fibroblasts (MEFs) to assess the role of Ada3 in DNA damage response following exposure to ionizing radiation (IR). We report that Ada3 depletion was associated with increased levels of phospho-ATM (pATM), gamma H2AX, phospho-53BP1 (p53BP1) and phospho-RAD51 (pRAD51) in untreated cells; however, radiation response was intact in Ada3(-/-) cells. Notably, Ada3(-/-) cells exhibited a significant delay in disappearance of DNA damage foci for several critical proteins involved in the DNA repair process. Significantly, loss of Ada3 led to enhanced chromosomal aberrations, such as chromosome breaks, fragments, deletions and translocations, which further increased upon DNA damage. Notably, the total numbers of aberrations were more clearly observed in S-phase, as compared with G(1) or G(2) phases of cell cycle with IR. Lastly, comparison of DNA damage in Ada3(fl/fl) and Ada3(-/-) cells confirmed higher residual DNA damage in Ada3(-/-) cells, underscoring a critical role of Ada3 in the DNA repair process. Taken together, these findings provide evidence for a novel role for Ada3 in maintenance of the DNA repair process and genomic stability.

• 出版日期2012-11-15