title: The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers.
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.
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chung
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Onyango
authors.affiliation: 1] 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.
authors.forename: Z
authors.initials: Z
authors.lastname: Guo
authors.affiliation: WWAMI Medical Education Program, School of Molecular Biosciences, Washington State University, Spokane, WA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Dai
authors.affiliation: 1] 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.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Pang
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 1] Section de Recherche, Institut Curie, CNRS UMR3244, Paris, France [2] Muséum National d'Histoire Naturelle, USM 503, INSERM U565, UMR7196, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Lopes
authors.affiliation: Section de Recherche, Institut Curie, CNRS UMR3244, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: WWAMI Medical Education Program, School of Molecular Biosciences, Washington State University, Spokane, WA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chai
authors.affiliation: Department of Surgery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Raz
authors.affiliation: Department of Medical Oncology and Therapeutics Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Reckamp
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Shen
mesh_terms: D019943:Amino Acid Substitution; D000782:Aneuploidy; D000818:Animals; D002460:Cell Line; D004261:DNA Replication / Q000235:genetics; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D000071657:Werner Syndrome Helicase
chemical_list: D004273:DNA, Neoplasm; D005090:Exodeoxyribonucleases; C572473:Fen1 protein, mouse; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse