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TIS21(/BTG2/PC3) accelerates the repair of DNA double strand breaks by enhancing Mre11 methylation and blocking damage signal transfer to the Chk2(T68)-p53(S20) pathway

Authors
Choi, KS; Kim, JY; Lim, SK; Choi, YW; Kim, YH; Kang, SY; Park, TJ; Lim, IK
Citation
DNA repair, 11(12):965-975, 2012
Journal Title
DNA repair
ISSN
1568-78641568-7856
Abstract
DNA double strand breaks (DSBs) occur more frequently in TIS21(-/-) mouse embryo fibroblasts than that in wild type MEFs (wt-MEFs). Therefore, the role TIS21 plays in the DNA damage response was investigated. Adenoviral transduction of Huh7 tumor cells with the TIS21 gene accelerated the repair of DSBs induced by etoposide treatment as evaluated by clearance of γH2AX foci and the Comet assay. TIS21 increased methylation of Mre11 and protein arginine methyltransferase 1 (PRMT1) activity, leading to Mre11 activation in vitro and in vivo, as determined by immunoprecipitation and radiolabeling analyses. When downstream DNA damage response mediators were evaluated in various human cancer cells lines, TIS21 was found to strongly inhibit Chk2(T68) and p53(S20) phosphorylation by p-ATM(S1981) but not p53(S15). The loss of Chk2 activation after etoposide treatment reduced apoptosis in the cells by downregulating the expression of E2F1 and Bax. These data suggest that TIS21 regulates DSB repair and apoptosis. Expression of TIS21 promoted the repair of DSBs and reduced apoptosis by blocking the damage signal from p-ATM(S1981) to Chk2(T68)-p53(S20)via the activation of Mre11 and PRMT1.
MeSH terms
Adenoviridae/genetics/metabolismApoptosisCloning, MolecularComet Assay*DNA Breaks, Double-StrandedDNA Methylation*DNA RepairDNA-Binding Proteins/genetics/*metabolismE2F1 Transcription Factor/genetics/metabolismEnzyme ActivationEtoposide/adverse effectsGenetic Vectors/genetics/metabolismHEK293 CellsHeLa CellsHistones/genetics/metabolismHumansImmediate-Early Proteins/genetics/*metabolismPhosphorylationProtein-Arginine N-Methyltransferases/genetics/metabolismProtein-Serine-Threonine Kinases/genetics/*metabolismRepressor Proteins/genetics/metabolismSignal TransductionTumor Suppressor Protein p53/genetics/metabolismTumor Suppressor Proteins/genetics/*metabolismbcl-2-Associated X Protein/genetics/metabolism
DOI
10.1016/j.dnarep.2012.09.009
PMID
23089312
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
박, 태준임, 인경
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