PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage

Jinfang Zhang, Yu-Ru Lee, Fabin Dang, Wenjian Gan, Archita Venugopal Menon, Jesse M. Katon, Chih-Hung Hsu, John M. Asara, Priyanka Tibarewal, Nicholas R. Leslie, Yang Shi, Pier Paolo Pandolfi, Wenyi Wei

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1306-1323
Number of pages18
JournalCancer discovery
Volume9
Issue number9
Early online date19 Jun 2019
DOIs
Publication statusPublished - Sep 2019

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    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., Shi, Y., Pandolfi, P. P., & Wei, W. (2019). PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage. Cancer discovery, 9(9), 1306-1323. https://doi.org/10.1158/2159-8290.CD-18-0083