WIP1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation

WIP1 phosphatase is emerging as an important regulator of tumorigenesis, but no unifying mechanistic network has been proposed. Here we found that WIP1 plays a key role in the transcriptional regulation of heterochromatin-associated DNA sequences in germ-line and cancer cells. WIP1 was required for epigenetic remodeling of repetitive DNA elements within the heterochromatin, including L1 LINE retrotransposons. Mechanistically, WIP1regulated an ATM-dependent increase in BRCA1 occupancy on L1 LINEs, resulting in closed chromatin without ubiquitination of histone H2A. This mechanism appeared to be dependent on the ability of BRCA1 to bind the heterochromatin protein HP1, the recruitment of DNA methyltransferases, and subsequent DNA methylation. Attenuation of ATM, in turn, reversed heterochromatin methylation in both germ-line and cancer cells. DNA methylation plays a central role in the generation of mutations in human tumors and we found that 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 DNA methylation and global heterochromatin silencing, and thus is critical in maintaining genome integrity during development and in cancer. Total RNA was extracted from control spermatids, Wip1-/- and Wip1-/- Atm+/- spermatids. The final cRNA samples were hybridized in triplicates to Illumina Mouse WG-6 v2.0 Expression arrays.