LAUSR

The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity by antagonizing the PI3K-Akt oncogenic pathway. However, molecular mechanism(s) underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSBs) promote PTEN interaction with MDC1, upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs also enhance NSD2 (MMSET/WHSC1)-mediated di-methylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN into DNA damage sites, governing efficient repair of DSBs partly through dephosphorylation of yH2AX. More importantly of note, inhibiting NSD2-mediated methylation of PTEN, either through expressing methylation-deficient PTEN mutants, or through inhibiting NSD2, sensitizes cancer cells to combinatorial treatment with PI3K inhibitor and DNA-damaging agents in both cell culture and in vivo xenograft models. Therefore, our study provides a novel molecular mechanism for PTEN regulation of DSBs repair in a methylation- and protein-phosphatase-dependent manner.