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Oncogene. 2015 Feb 12;34(7):902-11. doi: 10.1038/onc.2014.19. Epub 2014 Mar 10.

The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers.

Author information

  • 1Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • 21] Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA [2] Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
  • 3WWAMI Medical Education Program, School of Molecular Biosciences, Washington State University, Spokane, WA, USA.
  • 41] Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA [2] College of Life Science, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 5Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • 6Department of Pathology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • 71] Section de Recherche, Institut Curie, CNRS UMR3244, Paris, France [2] Muséum National d'Histoire Naturelle, USM 503, INSERM U565, UMR7196, Paris, France.
  • 8Section de Recherche, Institut Curie, CNRS UMR3244, Paris, France.
  • 9Department of Surgery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • 10Department of Medical Oncology and Therapeutics Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.

Abstract

Polymorphisms and somatic mutations in Flap Endonuclease 1 (FEN1), an essential enzyme involved in DNA replication and repair, can lead to functional deficiencies of the FEN1 protein and a predisposition to cancer. We identified a FEN1 germline mutation that changed residue E359 to K in a patient whose family had a history of breast cancer. We determined that the E359K mutation, which is in the protein-protein domain of FEN1, abolished the interaction of FEN1 with Werner syndrome protein (WRN), an interaction that is critical for resolving stalled DNA replication forks. Furthermore, although the flap endonuclease activity of FEN1 E359K was unaffected, it failed to resolve bubble structures, which require the FEN1 gap-dependent endonuclease activity. To determine the etiological significance of E359K, we established a mouse model containing this mutation. E359K mouse embryonic fibroblasts (MEF) were more sensitive to DNA crosslinking agents that cause replication forks to stall. Cytological analysis suggested that the FEN1-WRN interaction was also required for telomere stability; mutant cell lines had fragile telomeres, increased numbers of spontaneous chromosomal anomalies and higher frequencies of transformation. Moreover, the incidence of cancer was significantly higher in mice homozygous for FEN1 E359K than in wild-type mice, suggesting that the FEN1 E359K mutation is oncogenic.

PMID:
24608430
PMCID:
PMC4160428
DOI:
10.1038/onc.2014.19
[PubMed - indexed for MEDLINE]
Free PMC Article
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