科学研究
20190909 PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage
发布时间:2019-09-10  来源:  阅读次数:

Zhang, J., Lee, Y.R., Dang, F., Gan, W., Menon, A.V., Katon, J.M., Hsu, C.H., Asara, J.M., Tibarewal, P., Leslie, N.R., Pandolfi, P. P. and Wei. W.*(2019). PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage. Cancer discovery 9, 1306-1323.


Abstract

The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K-AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, governing efficient repair of DSBs partly through dephosphorylation of γH2AX. 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 a 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 DSB repair in a methylation- and protein phosphatase-dependent manner. SIGNIFICANCE: NSD2-mediated dimethylation of PTEN is recognized by the 53BP1 tudor domain to facilitate PTEN recruitment into DNA-damage sites, governing efficient repair of DNA DSBs. Importantly, inhibiting PTEN methylation sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor combined with DNA-damaging agents in both cell culture and in vivo xenograft models.This article is highlighted in the In This Issue feature, p. 1143.

原文链接:https://cancerdiscovery.aacrjournals.org/content/9/9/1306.long


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