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

Sameer Mirza, Bryan J. Katafiasz, Rakesh Kumar, Jun Wang, Shakur Mohibi, Smrati Jain, Channabasavaiah B Gurumurthy, Tej K. Pandita, Bhavana J Dave, Hamid Band, Vimla Band

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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/flmouse 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), γH2AX, 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 G1 or G 2 phases of cell cycle with IR. Lastly, comparison of DNA damage in Ada3fl/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.

Original languageEnglish (US)
Pages (from-to)4266-4274
Number of pages9
JournalCell Cycle
Volume11
Issue number22
DOIs
StatePublished - Nov 15 2012

Keywords

  • ATAC
  • Ada3
  • DNA repair
  • Nuclear foci
  • SAGA

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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