Doria Filipponi, Julius Muller, Alexander Emelyanov, and Dmitry V Bulavin
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673
Published online in Cancer Cell on 14 October 2013.
Please see also a preview for this article in Cancer Cell :
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 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.
Figure Legend: A model for Wip1 regulation of heterochromatin via ATM/BRCA1-dependent DNA methylation. Under normal conditions or upon Wip1 depletion (upper panel), ATM is activated resulting in BRCA1 phosphorylation and subsequent recruitment of a repressive complex containing DNMT3b and HP1γ to heterochromatin-associated sequences. This is critical for establishment and the maintenance of 5meC patterns. Upon Wip1 overexpression (lower panel), Wip1 continuously silences ATM, preventing BRCA1 phosphorylation and complex formation with HP1γ. In turn, unmethylated cytosine is a substrate of APOBEC/AID deaminases and is efficiently converted to uracil, creating a mismatch that is eventually repaired by the base-excision repair (BER) mechanisms. Under conditions of Wip1 overexpression, DNA is demethylated while BER is blocked thus facilitating the generation of C-to-T mutations.
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