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

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.

The WTX Tumor Suppressor Interacts with the Transcriptional Corepressor TRIM28

“…For instance, using single molecule RNA sequencing, we previously noted the massive and highly specific derepression of human satellite II (HSATII) pericentromeric repeats in multiple epithelial cancers (13). Similarly, re-expression of endogenous retroviral elements has been reported in several tumor types (32,33), and satellite repeats are aberrantly expressed in BRCA1 mutant breast cancers (34,35). Activation of retroelements may trigger chromosomal insertions and rearrangements, but they may also lead to the aberrant expression of protein-encoding genes whose regulatory sequences are normally corepressed with the repeat sequences.…”

Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways

“…Wild-type (WT) p53-induced phosphatase 1 (Wip1 or PPM1D) negatively regulates the activity of multiple tumour suppression processes, including the p53, ATM, p16 (INK4a) and ARF pathways 18,19 . Recently, Wip1 has been implicated in the regulation of global heterochromatin silencing and, thus, is critical for maintaining genome integrity 20 .…”

Rétrotransposons et cellules somatiques

“…Dans les cellules souches neuronales, la perte d'expression d'ATM, protéine impliquée dans la répara-tion des cassures double-brins d'ADN, entraîne, soit une augmentation du nombre d'insertions des rétrotrans-posons L1, soit l'insertion de copies plus longues [10]. De plus, ATM est aussi impliquée dans un mécanisme de méthylation des L1 par le contrôle qu'elle exerce sur la phosphorylation de la protéine BRCA1 (breast cancer 1 protein), essentielle au recrutement d'un complexe répresseur ciblant les séquences des L1 [24].…”