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Mol Cancer Res. 2018 Aug;16(8):1241-1254. doi: 10.1158/1541-7786.MCR-17-0581. Epub 2018 May 8.

PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF.

Author information

1
Department of Genetics, Yale University, New Haven, Connecticut.
2
Department of Experimental Pathology, Yale University, New Haven, Connecticut.
3
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
4
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
5
Department of Genetics, Yale University, New Haven, Connecticut. peter.glazer@yale.edu.

Abstract

DNA double-strand breaks (DSB) are the most cytotoxic DNA lesions, and up to 90% of DSBs require repair by nonhomologous end joining (NHEJ). Functional and genomic analyses of patient-derived melanomas revealed that PTEN loss is associated with NHEJ deficiency. In PTEN-null melanomas, PTEN complementation rescued the NHEJ defect; conversely, suppression of PTEN compromised NHEJ. Mechanistic studies revealed that PTEN promotes NHEJ through direct induction of expression of XRCC4-like factor (NHEJ1/XLF), which functions in DNA end bridging and ligation. PTEN was found to occupy the NHEJ1 gene promoter and to recruit the histone acetyltransferases, PCAF and CBP, inducing XLF expression. This recruitment activity was found to be independent of its phosphatase activity, but dependent on K128, a site of regulatory acetylation on PTEN. These findings define a novel function for PTEN in regulating NHEJ DSB repair, and therefore may assist in the design of individualized strategies for cancer therapy.Implications: PTEN is the second most frequently lost tumor suppressor gene. Here it is demonstrated that PTEN has a direct and novel regulatory role in NHEJ, a key DNA repair pathway in response to radiation and chemotherapy. Mol Cancer Res; 16(8); 1241-54. ©2018 AACR.

PMID:
29739874
PMCID:
PMC6072556
[Available on 2019-08-01]
DOI:
10.1158/1541-7786.MCR-17-0581

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