Nuclear accumulation of PTEN is required for DNA repair and sensitivity to DNA damage.

  • Major finding: Nuclear accumulation of PTEN is required for DNA repair and sensitivity to DNA damage.

  • Mechanism: PTEN is excluded from the nucleus after genotoxic stress in an ATM-dependent manner.

  • Impact:PTEN-deficient tumors may be sensitive to the combination of DNA damage and PI3K inhibition.

PTEN is a tumor suppressor gene frequently deleted in human cancers that encodes a negative regulator of phosphoinositide 3-kinase (PI3K) signaling. Although cytoplasmic inhibition of the PI3K pathway has been considered the main role of PTEN, PTEN can also localize to the nucleus, but the mechanism and functional significance of PTEN nuclear localization are unknown. Bassi and colleagues noted a high-molecular-weight version of PTEN in several cell types and determined that PTEN could be modified with a small ubiquitin-like modifier (SUMO) group at K254. Interestingly, a PTEN K254R mutant still inhibited PI3K signaling but no longer accumulated in the nucleus, indicating that SUMOylation of PTEN is specifically required for its nuclear localization. However, SUMOylated PTEN was excluded from the nucleus in response to ionizing radiation, prompting the authors to evaluate the role of nuclear PTEN in the DNA damage response. Cells expressing the PTEN K254R SUMOylation site mutant could not effectively resolve DNA double-strand breaks 24 hours after ionizing radiation and were deficient in homologous recombination-mediated DNA repair. Exclusion of SUMOylated PTEN from the nucleus after ionizing radiation was dependent on phosphorylation of S398 by ATM, providing further evidence that expulsion of nuclear PTEN is part of the DNA damage response. PTEN SUMOylation-defective cells also showed increased radiosensitivity, but PTEN-null cells did not, possibly because activation of PI3K in the complete absence of PTEN promotes survival. Based on these findings, the authors hypothesized that cells lacking PTEN should be sensitive to the combined use of a DNA damaging agent and a PI3K inhibitor and indeed found that the combination significantly and specifically reduced the growth of PTEN-deficient xenografts. These results therefore not only identify a role for nuclear PTEN but also provide support for combining PI3K inhibitors and genotoxic agents in patients with PTEN-deficient cancers.

Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, et al. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science 2013;341:395–9.