TY - JOUR
T1 - Alteration/deficiency in activation-3 (Ada3) plays a critical role in maintaining genomic stability
AU - Mirza, Sameer
AU - Katafiasz, Bryan J.
AU - Kumar, Rakesh
AU - Wang, Jun
AU - Mohibi, Shakur
AU - Jain, Smrati
AU - Gurumurthy, Channabasavaiah Basavaraju
AU - Pandita, Tej K.
AU - Dave, Bhavana J.
AU - Band, Hamid
AU - Band, Vimla
PY - 2012/11/15
Y1 - 2012/11/15
N2 - 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.
AB - 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.
KW - Ada3
KW - ATAC
KW - DNA repair
KW - Nuclear foci
KW - SAGA
UR - http://www.scopus.com/inward/record.url?scp=84869423477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869423477&partnerID=8YFLogxK
U2 - 10.4161/cc.22613
DO - 10.4161/cc.22613
M3 - Article
C2 - 23095635
AN - SCOPUS:84869423477
SN - 1538-4101
VL - 11
SP - 4266
EP - 4274
JO - Cell Cycle
JF - Cell Cycle
IS - 22
ER -