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

[werner syndrome]

Polymorphisms and somatic mutations in Flap Endonuclease 1 (FEN 1 ), an essential enzyme involved in DNA replication and repair , can lead to functional deficiencies of the FEN 1 protein and a predisposition to cancer . We identified a FEN 1 germline mutation that changed residue E 359 to K in a patient whose family had a history of breast cancer . We determined that the E 359 K mutation , which is in the protein-protein domain of FEN 1 , abolished the interaction of FEN 1 with Werner syndrome protein (WRN ), an interaction that is critical for resolving stalled DNA replication forks . Furthermore , although the flap endonuclease activity of FEN 1 E 359 K was unaffected , it failed to resolve bubble structures , which require the FEN 1 gap-dependent endonuclease activity . To determine the etiological significance of E 359 K , we established a mouse model containing this mutation . E 359 K mouse embryonic fibroblasts (MEF ) were more sensitive to DNA crosslinking agents that cause replication forks to stall . Cytological analysis suggested that the FEN 1 -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 FEN 1 E 359 K than in wild-type mice , suggesting that the FEN 1 E 359 K mutation is oncogenic .Oncogene advance online publication , 10 March 2014 ; doi :10 .1038 /onc .2014 .19 .

Diseases
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Diseases presenting "functional deficiencies of the fen1 protein" symptom

werner syndrome

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