TIS21/BTG2/PC3 accelerates the repair of DNA double strand breaks by enhancing Mre11 methylation and blocking damage signal transfer to the Chk2T68-p53S20 pathway

被引：29

作者：

Choi, Kyu-Sung ^{[1
]}

Kim, Ji Yeon ^{[1
]}

Lim, Seo-Kyung ^{[1
]}

Choi, Yong Won ^{[1
]}

Kim, Young Hwa ^{[1
]}

Kang, So Young ^{[1
]}

Park, Tae Jun ^{[1
]}

Lim, In Young ^{[1
]}

机构：

[1] Ajou Univ, Sch Med, Dept Biochem & Mol Biol, Brain Korea Div Cell Transformat & Restorat 21, Suwon 443721, South Korea

来源：

DNA REPAIR | 2012年 / 11卷 / 12期

基金：

新加坡国家研究基金会;

关键词：

TIS21(/BTG2/PC3); Chk2(T68); pS3(S20); PRMT1; Mre11; methylation; DNA damage; CELL-CYCLE CHECKPOINTS; ARGININE METHYLATION; TUMOR-SUPPRESSOR; PROTEIN-KINASE; MRN COMPLEX; GENE PC3; P53; ATM; ACTIVATION; CHK2;

D O I：

10.1016/j.dnarep.2012.09.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 gamma H2AX 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. (C) 2012 Elsevier B.V. All rights reserved.

引用

页码：965 / 975

页数：11

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