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Repo-Man Controls a Protein Phosphatase 1-Dependent Threshold for DNA Damage Checkpoint Activation

阿平添加于 2010-3-2 22:07 | 2278 次阅读 | 0 个评论

作者
Peng A, Lewellyn AL, Schiemann WP, Maller JL
摘要
BACKGROUND: In response to DNA damage, cells activate checkpoints to halt cell-cycle progression and prevent genomic instability. Checkpoint activation induced by DNA double-strand breaks (DSB) is dependent on the ATM kinase, a master regulator of the DNA damage response (DDR) that is activated through autophosphorylation and monomerization. RESULTS: Here we show that either protein phosphatase 1 or 2A is sufficient to suppress activation of the DDR and that simultaneous inhibition of both phosphatases fully activates the response. PP1-dependent DDR regulation is mediated by its chromatin-targeting subunit, Repo-Man. Studies in Xenopus egg extracts demonstrate that Repo-Man interacts with ATM and PP1 through distinct domains, leading to PP1-dependent regulation of ATM phosphorylation and activation. Consequently, the level of Repo-Man determines the activation threshold of the DNA damage checkpoint. Repo-Man interacts and extensively colocalizes with ATM in human cells. Expression of wild-type, but not PP1 binding-deficient, Repo-Man attenuates DNA damage-induced ATM activation. Moreover, Repo-Man dissociates from active ATM at DNA damage sites, suggesting that activation of the DDR involves removal of inhibitory regulators. Analysis of primary tumor tissues and cell lines demonstrates that Repo-Man is frequently upregulated in many types of cancers. Elevated Repo-Man expression blunts DDR activation in precancerous cells, whereas knockdown of Repo-Man in malignant cancer cells resensitizes the DDR and restrains growth in soft agar. CONCLUSIONS: We report essential DDR regulation mediated by Repo-Man-PP1 and further delineate underlying mechanisms. Moreover, our evidence suggests that elevated Repo-Man contributes to cancer progression.
详细资料
- 文献种类: Journal Article
- 期刊名称: Current Biology : CB
- 期刊缩写: Curr Biol
- 期卷页: 2010年
- 地址: Howard Hughes Medical Institute, University of Colorado School of Medicine, Aurora, CO 80045, USA
- ISBN: 0960-9822
- 备注:PMID:20188555
学科领域生物医药 » 生物学
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Repo-Man PP1 DDR
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