title: 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.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Division of Cell Transformation and Restoration, Ajou University, School of Medicine, Suwon 443-721, Republic of Korea.
authors.forename: Kyu-Sung
authors.initials: KS
authors.lastname: Choi
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Seo-Kyung
authors.initials: SK
authors.lastname: Lim
authors.forename: Yong Won
authors.initials: YW
authors.lastname: Choi
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Kim
authors.forename: So Young
authors.initials: SY
authors.lastname: Kang
authors.forename: Tae Jun
authors.initials: TJ
authors.lastname: Park
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D064447:Checkpoint Kinase 2; D003001:Cloning, Molecular; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005047:Etoposide / Q000009:adverse effects; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D000076228:MRE11 Homologue Protein; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C468783:H2AX protein, human; D006657:Histones; D017874:Immediate-Early Proteins; C121766:MRE11 protein, human; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C070114:BTG2 protein, human; D005047:Etoposide; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein