The FEN1 L209P mutation interferes with long-patch base excision repair and induces cellular transformation.
Flap endonuclease-1 (FEN1) is a multifunctional, structure-specific nuclease that has a critical role in maintaining human genome stability. FEN1 mutations have been detected in human cancer specimens and have been suggested to cause genomic instability and cancer predisposition. However, the exact relationship between FEN1 deficiency and cancer susceptibility remains unclear. In the current work, we report a novel colorectal cancer-associated FEN1 mutation, L209P. This mutant protein lacks the FEN, exonuclease (EXO) and gap endonuclease (GEN) activities of FEN1 but retains DNA-binding affinity. The L209P FEN1 variant interferes with the function of the wild-type FEN1 enzyme in a dominant-negative manner and impairs long-patch base excision repair in vitro and in vivo. Expression of L209P FEN1 sensitizes cells to DNA damage, resulting in endogenous genomic instability and cellular transformation, as well as tumor growth in a mouse xenograft model. These data indicate that human cancer-associated genetic alterations in the FEN1 gene can contribute substantially to cancer development.
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Sun
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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He
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Wu
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Pan
The Second Hospital of Nanjing, The Second Affiliated Hospital of Southeast University, Nanjing, China.
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Wu
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Zhao
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Hu
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Sekhar
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Li
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Zheng
Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Chen
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.|Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Shen
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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Guo
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D045585:Flap Endonucleases / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D011485:Protein Binding
D045585:Flap Endonucleases; C468317:FEN1 protein, human