Wip1 Controls Global Heterochromatin Silencing via ATM/BRCA1-Dependent DNA Methylation

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Wip1 Controls Global Heterochromatin Silencing via ATM/BRCA1-Dependent DNA Methylation
Title:
Wip1 Controls Global Heterochromatin Silencing via ATM/BRCA1-Dependent DNA Methylation
Other Titles:
Cancer Cell
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Publication Date:
14 October 2013
Citation:
Wip1 Controls Global Heterochromatin Silencing via ATM/BRCA1-Dependent DNA Methylation Filipponi, Doria et al. Cancer Cell, Volume 24, Issue 4, 528 - 541
Abstract:
Wip1 phosphatase is emerging as an important regulator of tumorigenesis, but no unifying mechanistic network has been proposed. We found that Wip1 plays a key role in the transcriptional regulation of heterochromatin-associated DNA sequences. Wip1 was required for epigenetic remodeling of repetitive DNA elements through regulation of BRCA1 interaction with HP1, the recruitment of DNA methyltransferases, and subsequent DNA methylation. Attenuation of ATM, in turn, reversed heterochromatin methylation. This mechanism was critical for the recruitment of the AID cytidine deaminase, and Wip1 levels strongly correlated with C-to-T substitutions and a total mutation load in primary breast cancers. We propose that Wip1 plays an important role in the regulation of global heterochromatin silencing and thus is critical in maintaining genome integrity.
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PublisherCopyrights
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ISSN:
1535-6108
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